Method for producing 1-substituted-1,2,3-triazole derivative

ABSTRACT

A method for producing a compound of the formula:                    
     (1) in a secondary or tertiary alcohol in the presence of a base, or 
     (2) in the absence of a base is provided. According to this method, a 1-substituted-1,2,3-triazole compound having a tyrosine kinase inhibitory action can be produced efficiently in a high yield at an industrial large scale by a convenient method

This application is a 371 of PCT/JP01/06145 filed Jul. 16, 2001.

TECHNICAL FIELD

The present invention relates to production methods of intermediates for1-substituted-1,2,3-triazole compounds having an inhibitory action ongrowth factor receptor tyrosine kinases (especially HER2) useful aspharmaceutical agents.

BACKGROUND ART

As a production method of an intermediate for a1-substituted-1,2,3-triazole compound having a tyrosine kinaseinhibitory action, for example, there is mentioned a method comprisingcondensing compound (1) of the following formula and compound (2) of thefollowing formula in the presence of a base in a solvent inert to thereaction (e.g., aromatic hydrocarbons such as benzene, toluene, xyleneetc., ethers such as tetrahydrofuran, dioxane etc., ketones such asacetone, 2-butanone etc., halogenated hydrocarbons such as chloroform,dichloromethane etc., N,N-dimethylformamide, dimethyl sulfoxide, and amixed solvent of these) to give the objective compound (3)(JP-A-11-60571, WO 98/03505):

wherein W₁ is a leaving group, R⁰ is an optionally substituted aromaticheterocyclic group, X1 is an oxygen atom, an optionally oxidized sulfuratom, —C(=O)—or —CH(OH)—, Y₁ is CH or N, ml is an integer of 0 to 10, n1is an integer of 1 to 5, the cyclic group

is an optionally substituted aromatic azole group and the ring A1 may befurther substituted.

In addition, as a production method of a 1-alkyl-1,2,3-triazolecompound, for example, there is mentioned a method comprising reactingthe compound (b2) of the following formula and the compound (b3) of thefollowing formula in the presence or absence of a base (JP-A-5-170763):

wherein R₁, R₂, R₃, R₄ and R₈ are the same or different and each is ahydrogen atom or a lower alkyl group, R₂ and R₃ in combination may form,together with the carbon atoms to which they are bonded, a cyclopentanering or a cyclohexane ring, R₅, R₆ and R₇ are the same or different andeach is a hydrogen atom, a halogen atom, a lower alkyl group optionallysubstituted by halogen atom(s) or a lower alkoxy group optionallysubstituted by halogen atom(s), Y₂ is a halogen atom, a lower alkylsulfonyloxy group or an aryl sulfonyloxy group, and R₉ is a 5 or6-membered heterocyclic group having 1 to 3 nitrogen atom(s), andwherein a 1H-1,2,4-triazole group is excluded and the heterocyclic groupis optionally substituted by 1 to 3, the same or different halogenatom(s), lower alkyl group(s) or lower alkoxy group(s).

The aforementioned conventional production methods pose problems in thatthey show low reaction selectivity, and therefore, a low yield. A methodusing a silver salt of 1H-1,2,3-triazole shows fine selectivity butrequires expensive starting materials. Therefore, there is a demand foran industrially advantageous production method of an intermediate for a1-substituted-1,2,3-triazole compound having an inhibitory action ongrowth factor receptor tyrosine kinases (especially HER2).

As a production method for obtaining a 1,2,3-triazole compound useful asa starting material of pharmaceutical agents or an intermediate forprinting, image processing agents, by the use of a hydrazone derivative,there is known, for example, a method comprising reacting compound (c1)of the following formula and compound (c2) under neutral or basicconditions to give compound (3) (JP-A-8-53425):

In the above formulas, R^(1c) is a lower alkyl group optionallysubstituted by halogen atom(s), a phenyl group wherein benzene ring isoptionally substituted by at least one substituent selected from halogenatom, lower alkyl group and lower alkoxy group, a benzyl group whereinbenzene ring is optionally substituted by at least one substituentselected from halogen atom, lower alkyl group and lower alkoxy group, alower alkylamino group wherein alkyl group is optionally substituted byhalogen atom, a phenylamino group wherein benzene ring is optionallysubstituted by at least one substituent selected from halogen atom,lower alkyl group and lower alkoxy group, an ammonium group that forms asalt with an inorganic acid or a carboxyl group that forms a salt withammonia; X is a halogen atom; R^(2c) and R^(3c) are each a hydrogen atomor a lower alkyl group optionally substituted by halogen atom(s); andR^(4c) is a lower alkyl group optionally substituted by halogen atom(s)or a phenyl group wherein benzene ring is optionally substituted by atleast one substituent selected from halogen atom, lower alkyl group andlower alkoxy group.

As a production method of an amine compound such as the above-mentionedcompound (c1), there is known a method comprising reacting phthalimidebutyryl chloride and chlorobenzene in the presence of anhydrous aluminumchloride, and treating the obtained 4-chloro-4-phthalimide butyrophenonewith acetic acid and hydrochloric acid to give4-chloro-4-aminobutyrophenone hydrochloride [Journal of MedicinalChemistry (J. Med. Chem.), vol. 9, pp. 945-949 (1966)].

The conventional production method for obtaining the aforementionedcompound (c3) showed lower yield from the compound (c1). A conventionalproduction method for obtaining an amine compound, such as compound(c1), poses a problem in that it requires many steps. Therefore, thereis a demand for an industrially advantageous production method of anintermediate for a 1-substituted-1,2,3-triazole compound having aninhibitory action on growth factor receptor tyrosine kinase (especially,HER2).

DISCLOSURE OF THE INVENTION

The present inventors have studied various production methods of1-substituted-1,2,3-triazole derivatives, and first found that areaction in a secondary or tertiary alcohol in the presence of a base ora reaction in the absence of a base unexpectedly results in theselective production of the objective 1-substituted-1,2,3-triazolederivative in a high yield, and that this production method is fullysatisfactory on an industrial scale, based on which they intensivelyinvestigated and completed the present invention.

They have also found that a reaction of an alkylamine compound and ahydrazone derivative, followed by a treatment with a base, unexpectedlyresults in the selective production of the objective1-substituted-1,2,3-triazole derivative in a high yield, and that thisproduction method is fully satisfactory on an industrial scale, based onwhich they intensively investigated and completed the present invention.

Further, the present inventors have found that a production method via aprotected 4-hydroxymethyloxazole compound as an intermediateunexpectedly results in the production of the objective product in ahigh yield, and that this production method is fully satisfactory on anindustrial scale, based on which they intensively investigated andcompleted the present invention.

Accordingly, the present invention provides the following.

1. A method for producing a compound of the formula:

wherein

R^(a1) and R^(a2) are each a hydrogen atom, a substituted hydroxy, asubstituted thiol, a substituted amino, an optionally substitutedhydrocarbon group, an optionally substituted heterocyclic group or anacyl;

R^(a3) is a group of the formula:

 wherein R^(a4) and R^(a5) are each a hydrogen atom, an optionallysubstituted hydroxy, an optionally substituted thiol, an optionallysubstituted amino, an optionally substituted hydrocarbon group, anoptionally substituted heterocyclic group or an acyl, or R^(a4) andR^(a5) in combination form oxo, R^(a6) is an optionally substitutedaromatic group, and m^(a) is an integer of 0 to 10; or

two or three from R^(a1), R^(a2) and R^(a3) form an optionallysubstituted ring, together with the adjacent carbon atom; and

R^(a7) and R^(a8) are each a hydrogen atom, a halogen, an optionallysubstituted hydroxy, an optionally substituted thiol, an optionallysubstituted amino, an optionally substituted hydrocarbon group, anoptionally substituted heterocyclic group or an acyl,

which method comprises reacting a compound of the formula:

wherein X^(a) is a leaving group and other symbols are as defined above,or a salt thereof [hereinafter to be also referred briefly to ascompound (aII)] and a compound of the formula:

wherein each symbol is as defined above, or a salt thereof,

(1) in a secondary or tertiary alcohol in the presence of a base, or

(2) in the absence of a base.

2. The production method of the aforementioned 1, which comprisesreaction in a secondary or tertiary alcohol in the presence of a base.

3. The production method of the aforementioned 1, which comprisesreaction in a tertiary alcohol in the presence of a base.

4. The production method of 1 above, wherein R^(a1) is a hydrogen atom.

5. The production method of 1 above, wherein R^(a1) and R^(a2) are eacha hydrogen atom.

6. The production method of 1 above, wherein R^(a3) is a group of theformula:

wherein each symbol is as defined in the aforementioned 1.

7. The production method of 6 above, wherein R^(a4) and R^(a5) are eacha hydrogen atom.

8. The production method of 6 above, wherein R^(a6) is an optionallysubstituted phenyl.

9. The production method of 6 above, wherein m^(a) is 3.

10. The production method of 1 above, wherein R^(a7) and R^(a8) are eacha hydrogen atom.

11. A salt of a compound of the formula:

12. A compound of the formula:

wherein X^(a′) is a halogen atom, OSO₂R^(a) or OCOR^(a) wherein R^(a) isan optionally substituted hydrocarbon group [hereinafter to be referredto as compound (aIIa)].

13. A method for producing compound (aIIa), which comprises reacting acompound of the formula:

wherein M^(a) is a hydrogen atom, an alkali metal atom or an alkalineearth metal atom [hereinafter to be referred to as compound (aII′)],and 1) thionyl halide [hereinafter to be referred to as compound (aa)],2) oxalyl halide [hereinafter to be referred to as compound (ab)], 3) acompound of the formula:

R^(a)SO₂X^(a) or (R^(a)SO₂)₂O

wherein R^(a) is an optionally substituted hydrocarbon group and X^(a)is a leaving group [hereinafter to be referred to as compound (ac)] or4) a compound of the formula:

R^(a)COX^(a) or (R^(a)CO)₂O

wherein R^(a) and X^(a) are as defined above [hereinafter to be referredto as compound (ad)] under basic conditions.

14. A compound of the formula:

or a salt thereof [hereinafter to be also referred to as compound(aIe)].

15. The production method of the aforementioned 1 wherein R^(a1),R^(a2), R^(a7) and R^(a8) are each a hydrogen atom and R^(a3) is3-[4-(t-butoxyphenyl)]propyl.

16. A method for producing a compound of the formula:

which comprises reacting a compound of the formula:

wherein M^(a) is a hydrogen atom, an alkaline metal atom or an alkalineearth metal atom, and 1) thionyl halide, 2) oxalyl halide, 3) a compoundof the formula:

R^(a)SO₂X^(a) or (R^(a)SO₂)₂O

wherein R^(a) is an optionally substituted hydrocarbon group and X^(a)is a leaving group or 4) a compound of the formula:

R^(a)COX^(a) or (R^(a)CO)₂O

wherein R^(a) and X^(a) are as defined above, under basic conditions togive a compound of the formula:

wherein X^(a′) is a halogen atom, OSO₂R^(a) or OCOR^(a) wherein R^(a) isas defined above, and reacting this compound with a compound of theformula:

or a salt thereof, (1) in the presence of a base in a secondary ortertiary alcohol, or

(2) in the absence of a base to give a compound of the formula:

and deprotecting this compound.

17. A method for producing a compound of the formula:

which comprises deprotecting a compound of the formula:

18. A method for producing a compound of the formula:

which comprises deprotecting a compound of the formula:

19. A method for producing a compound of the formula:

wherein R^(b1), R^(b2) and R^(b3) are each a hydrogen atom, anoptionally substituted hydroxy, an optionally substituted thiol, anoptionally substituted amino, an optionally substituted hydrocarbongroup, an optionally substituted heterocyclic group or an acyl, or twoor three from R^(b1), R^(b2) and Rb³ form, together with the adjacentcarbon atom, an optionally substituted ring, and R^(b4) and R^(b5) areeach a hydrogen atom, an optionally substituted hydroxy, an optionallysubstituted thiol, an optionally substituted amino, an optionallysubstituted hydrocarbon group, an optionally substituted heterocyclicgroup or an acyl, and R^(b6) is an optionally substituted alkyl or anoptionally substituted phenyl, or a salt thereof [hereinafter to be alsoreferred to as compound (bI)], which comprises reacting a compound ofthe formula:

wherein each symbol is as defined above, or a salt thereof [hereinafterto be also referred to as compound (bII)] and a compound of the formula:

wherein X^(b1) and Xb² are each a halogen, and R^(b4), R^(b5) and R^(b6)are as defined above, or a salt thereof, [hereinafter also to bereferred to as compound (bIII)] and treating the reaction mixture with abase.

20. The production method of 19 above, wherein R^(b1) is a hydrogenatom.

21. The production method of 19 above, wherein R^(b1) and R^(b2) areeach a hydrogen atom.

22. The production method of the aforementioned 19, wherein R^(b3) is agroup of the formula:

wherein R^(b7) and R^(b8) are each a hydrogen atom, an optionallysubstituted hydroxy, an optionally substituted thiol, an optionallysubstituted amino, an optionally substituted hydrocarbon group, anoptionally substituted heterocyclic group or an acyl, or R^(b7) andR^(b8) in combination form oxo, R^(b9) is an optionally substitutedaromatic group, and mb is an integer of 0 to 10.

23. The production method of 22 above wherein R^(b7) and R^(b8) are eacha hydrogen atom, R^(b9) is an optionally substituted phenyl, and m^(b)is 3.

24. The production method of 23 above wherein R^(b1) and R^(b2) are eacha hydrogen atom.

25. The production method of 19 above wherein R^(b4) and R^(b5) are eacha hydrogen atom.

26. The production method of 19 above wherein R^(b6) is a phenylsubstituted by alkyl.

27. A method for producing a compound of the formula:

wherein, R^(b10) is an optionally substituted amino, an optionallysubstituted hydrocarbon group, an optionally substituted heterocyclicgroup or an acyl, R^(b11) is a substituent, n^(b) is an integer of 0 to4, and R^(b12) is an optionally substituted alkylene, an optionallysubstituted alkenylene or an optionally substituted alkynylene, or asalt thereof, which comprises reacting a compound of the formula:

wherein each symbol is as defined above, or a salt thereof [hereinafterto be also referred to as compound (bIV)] and a compound of the formula:

HOOC—R^(b12)—NH₂  (bV)

wherein R^(b12) is as defined above, a salt thereof or a reactivederivative thereof [hereinafter to be also referred to as compound(bV)].

28. A method for producing a compound of the formula:

wherein each symbol is as defined above, or a salt thereof [hereinafterto be also referred to as compound (bVII)], which comprises reactingcompound (bIV) and compound (bV), and reducing the obtained compound(bVI) or a salt thereof.

29. A method for producing a compound of the formula:

wherein each symbol is as defined above, or a salt thereof [hereinafterto be also referred to as compound (bVIII)], which comprises reactingcompound (bIV) and compound (bV), reducing the obtained compound (bVI)or a salt thereof, reacting the obtained compound (bVII) and compound(bIII), and treating the reaction mixture with a base.

30. The production method of 29 above, wherein R^(b4) and R^(b5) areeach a hydrogen atom, R^(b10) is a C₁₋₃ alkyl, R^(b12) is a trimethyleneand n^(b) is 0.

31. A trifluoromethanesulfonate of a compound of the formula:

wherein R^(b12′) is trimethylene and other symbols are as defined in theaforementioned 27.

32. A method for producing a compound of the formula:

wherein Ar^(c) is an optionally substituted aromatic group, R^(c1) andR^(c2) are each a hydrogen atom or a lower alkyl, R^(c3) and R^(c4) areeach a hydrogen atom or a lower alkyl, Y^(c) is C, S or SO and R^(c5) isa hydrogen atom, a lower alkyl, an optionally substituted phenyl, anoptionally substituted benzyloxy or an optionally substitutedbenzylamino, or a salt thereof [hereinafter to be also referred to ascompound (cIV)], which comprises reacting a reaction mixture of acompound of the formula:

wherein each symbol is as defined above, or a salt thereof [hereinafterto be also referred to as compound (cI)] and a compound of the formula:

wherein X^(c1) and X^(c2) are each a halogen, and other symbols are asdefined above, or a salt thereof [hereinafter to be also referred to ascompound (cII)] with a compound of the formula:

wherein M^(c) is a hydrogen atom or a metal, and other symbols are asdefined above, or a salt thereof [hereinafter to be also referred to ascompound (cIII)].

33. The production method of 32 above, wherein Ar^(c) is4-trifluoromethylphenyl.

34. The production method of 32 above, wherein R^(c1), R^(c2), R^(c3)and R^(c4) are each a hydrogen atom and R^(c5) is methyl.

36. A method for producing a compound of the formula:

wherein each symbol is as defined above, or a salt thereof [hereinafterto be also referred to as compound (cVII)], which comprises subjectingcompound (cIV) to hydrolysis or catalytic reduction, subjecting theobtained compound of the formula:

wherein each symbol is as defined above, or a salt thereof [hereinafterto be also referred to as compound (cV)] to sulfonylation orhalogenation, and reacting the compound with a compound of the formula:

wherein n^(c) is an integer of 1 to 10, or a salt thereof [hereinafterto be also referred to as compound (cVI)].

37. The production method of 36 above, wherein Ar^(c) is4-trifluoromethylphenyl.

38. The production method of 36 above, wherein R^(c1), R^(c2), R^(c3)and R^(c4) are each a hydrogen atom, R^(c5) is methyl and n^(c) is 4.

39. A method for producing compound (cVII) or a salt thereof, whichcomprises reacting a reaction mixture of compound (cI) and compound(cII) with compound (cIII), subjecting the resulting compound tohydrolysis or catalytic reduction, subjecting the obtained compound (cV)to sulfonylation or halogenation, and reacting the compound withcompound (cVI).

40. The production method of 39 above, wherein Ar^(c) is4-trifluoromethylphenyl.

41. The production method of 39 above, wherein R^(c1), R^(c2), R^(c3)and R^(c4) are each a hydrogen atom, R^(c5) is methyl and n^(c) is 4.

42. A method for producing a compound of the formula:

wherein each symbol is defined above, or a salt thereof, which comprisessubjecting a reaction mixture of a compound of the formula:

wherein each symbol is as defined in the aforementioned 32 or a saltthereof and compound (cII) or a salt thereof to hydrolysis, subjectingthe obtained compound of the formula:

wherein each symbol is as defined above or a salt thereof tosulfonylation or halogenation, and reacting the resulting compound withcompound (cVI) or a salt thereof.

43. A method for producing compound (cVIIa) or a salt thereof, whichcomprises reacting a reaction mixture of compound (cIa) or a saltthereof and compound (cII) or a salt thereof with compound (cVI) or asalt thereof.

44. A compound of the formula:

45. A method for producing compound (cVIIa) or a salt thereof, whichcomprises subjecting the compound (cVa) or a salt thereof tosulfonylation or halogenation, and reacting the resulting compound withcompound (cVI) or a salt thereof.

46.1-[4-[4-[[2-[(E)-2-[4-(Trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole.

47. The crystal of the aforementioned 46, having characteristic peaks atdiffraction angles of about 6.98, 14.02, 17.56, 21.10 and 24.70 degreesin powder X-ray diffraction.

48. A pharmaceutical composition comprising the crystal of theaforementioned 46.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a powder X-ray diffraction chart of the compound obtained inReference Example 22.

FIG. 2 is a powder X-ray diffraction chart of the compound obtained inExample 30.

DETAILED DESCRIPTION OF THE INVENTION

In this specification, the “hydrocarbon group” of the “an optionallysubstituted hydrocarbon group” is exemplified by chain or cyclichydrocarbon group (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, aryl,aralkyl etc.) and the like, with preference given to chain or cyclichydrocarbon group having 1 to 16 carbon atoms.

Examples of the “alkyl” preferably include, for example, C₁₋₆ alkyl(e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl etc.) and the like.

Examples of the “alkenyl” preferably include, for example, C₂₋₆ alkenyl(e.g., vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl,2-methyl-2-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl etc.) andthe like.

Examples of the “alkynyl” preferably include, for example, C₂₋₆ alkynyl(e.g., ethynyl, propargyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-hexynyletc.) and the like.

Examples of the “cycloalkyl” preferably include, for example, C₃₋₆cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.)and the like.

Examples of the “aryl” preferably include, for example, C₆₋₁₄ aryl(e.g., phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl,4-biphenylyl, 2-anthryl etc.) and the like.

Examples of the “aralkyl” preferably include, for example, C₇₋₁₆ aralkyl(e.g., benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl,2-naphthylmethyl; 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl,5-phenylpentyl etc.) and the like.

The “substituent” of said “optionally substituted hydrocarbon group oraromatic group” is exemplified by halogen atom (e.g., fluorine,chlorine, bromine, iodine etc.), C₁₋₃ alkylenedioxy (e.g.,methylenedioxy, ethylenedioxy etc.), nitro, cyano, optionallyhalogenated C₁₋₆ alkyl, optionally halogenated C₂₋₆ alkenyl, optionallyhalogenated C₂₋₆ alkynyl, optionally halogenated C₃₋₆ cycloalkyl,optionally substituted C₆₋₁₄ aryl, optionally halogenated C₁₋₆ alkoxy,C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkoxy (e.g., ethoxycarbonylmethyloxy etc.),hydroxy, C₆₋₁₄ aryloxy (e.g., phenyloxy, 1-naphthyloxy, 2-naphthyloxyetc.), C₇₋₁₆ aralkyloxy (e.g., benzyloxy, phenethyloxy etc.), mercapto,optionally halogenated C₁₋₆ alkylthio, C₆₋₁₄ arylthio (e.g., phenylthio,1-naphthylthio, 2-naphthylthio etc.), C₇₋₁₆ aralkylthio (e.g.,benzylthio, phenethylthio etc.), amino, mono-C₁₋₆ alkylamino (e.g.,methylamino, ethylamino etc.), mono-C₆₋₁₄ arylamino (e.g., phenylamino,1-naphthylamino, 2-naphthylamino etc.), di-C₁₋₆ alkylamino (e.g.,dimethylamino, diethylamino, ethylmethylamino etc.), di-C₆₋₁₄ arylamino(e.g., diphenylamino etc.), formyl, carboxy, C₁₋₆ alkyl-carbonyl (e.g.,acetyl, propionyl etc.), C₃₋₆ cycloalkyl-carbonyl (e.g.,cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl etc.), C₁₋₆alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,tert-butoxycarbonyl etc.), C₆₋₁₄ aryl-carbonyl (e.g., benzoyl,1-naphthoyl, 2-naphthoyl etc.), C₇₋₁₆ aralkyl-carbonyl (e.g.,phenylacetyl, 3-phenylpropionyl etc.), C₆₋₁₄ aryloxy-carbonyl (e.g.,phenoxycarbonyl etc.), C₇₋₁₆ aralkyloxy-carbonyl (e.g.,benzyloxycarbonyl, phenethyloxycarbonyl etc.), 5 or 6-memberedheterocyclic carbonyl (e.g., nicotinoyl, isonicotinoyl, thenoyl, furoyl,morpholinocarbonyl, thiomorpholinocarbonyl, piperazin-1-ylcarbonyl,pyrrolidin-1-ylcarbonyl etc.), carbamoyl, mono-C₁₋₆ alkyl-carbamoyl(e.g., methylcarbamoyl, ethylcarbamoyl etc.), di-C₁₋₆ alkyl-carbamoyl(e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl etc.),C₆₋₁₄ aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl,2-naphthylcarbamoyl etc.), 5 or 6-membered heterocyclic carbamoyl (e.g.,2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl,2-thienylcarbamoyl, 3-thienylcarbamoyl etc.), C₁₋₆ alkylsulfonyl (e.g.,methylsulfonyl, ethylsulfonyl etc.), C₆₋₁₄ arylsulfonyl (e.g.,phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl etc.),formylamino, C₁₋₆ alkylcarbonylamino (e.g., acetylamino etc.), C₆₋₁₄aryl-carbonylamino (e.g., benzoylamino, naphthoylamino etc.), C₁₋₆alkoxycarbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino,propoxycarbonylamino, butoxycarbonylamino etc.), C₁₋₆ alkylsulfonylamino(e.g., methylsulfonylamino, methylsulfonylamino etc.), C₆₋₁₄arylsulfonylamino (e.g., phenylsulfonylamino, 2-naphthylsulfonylamino,1-naphthylsulfonylamino etc.), C₁₋₆ alkyl-carbonyloxy (e.g., acetoxy,propionyloxy etc.), C₆₋₁₄ aryl-carbonyloxy (e.g., benzoyloxy,naphthylcarbonyloxy etc.), C₁₋₆ alkoxy-carbonyloxy (e.g.,methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy,butoxycarbonyloxy etc.), mono-C₁₋₆ alkyl-carbamoyloxy (e.g.,methylcarbamoyloxy, methylcarbamoyloxy etc.), di-C₁₋₆ alkyl-carbamoyloxy(e.g., dimethylcarbamoyloxy, diethylcarbamoyloxy etc.), C₆₋₁₄aryl-carbamoyloxy (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy etc.),nicotinoyloxy, 5 to 7-membered saturated cyclic amino (e.g.,pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, thiomorpholino,tetrahydroazepin-1-yl etc.), 5 to 10-membered aromatic heterocyclicgroup (e,g., 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-oxazolyl,4-oxazolyl, 5-oxazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl,8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl,2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 1-imidazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyridazinyl, 3-isothiazolyl,3-isooxazolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl,2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl,3-benzo[b]furanyl etc.) and the like.

The “hydrocarbon group” may have 1 to 5, preferably 1 to 3, for example,the above-mentioned substituents at substitutable position(s). When thenumber of the substituents is two or more, the respective substituentsmay be the same or different.

The aforementioned “optionally halogenated C₁₋₆ alkyl” is exemplified byC₁₋₆ alkyl optionally having 1 to 5, preferably 1 to 3, halogen atom(s)(e.g., fluorine, chlorine, bromine, iodine etc.), such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl andhexyl, and the like. Specifically, for example, methyl, chloromethyl,difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl,isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl,6,6,6-trifluorohexyl and the like are mentioned.

As the aforementioned “optionally halogenated C₂₋₆ alkenyl”, forexample, C₂₋₆ alkenyl optionally having 1 to 5, preferably 1 to 3,halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine etc.) ismentioned, such as vinyl, propenyl, isopropenyl, 2-buten-1-yl,4-penten-1-yl and 5-hexen-1-yl, and the like.

As the aforementioned “optionally halogenated C₂₋₆ alkynyl”, forexample, C₂₋₆ alkynyl optionally having 1 to 5, preferably 1 to 3,halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine etc.) ismentioned, such as 2-butyn-1-yl, 4-pentyn-1-yl and 5-hexyn-1-yl), andthe like.

As the aforementioned “optionally halogenated C₃₋₆ cycloalkyl”, forexample, C₃₋₆ cycloalkyl optionally having 1 to 5, preferably 1 to 3,halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine etc.) ismentioned, such as (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,and the like. Specifically, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl,2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl are mentioned.

As the “C₆₋₁₄ aryl” of the aforementioned “optionally substituted C₆₋₁₄aryl”, for example, phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl,3-biphenylyl, 4-biphenylyl, 2-anthryl and the like are mentioned.

As the “substituent” of the aforementioned “optionally substituted C₆₋₁₄aryl”, for example, 1 to 5 from halogen, hydroxy, optionally halogenatedC₁₋₆ alkyl, optionally halogenated C₁₋₆ alkoxy and the like can bementioned.

As the aforementioned “optionally halogenated C₁₋₆ alkoxy”, for example,C₁₋₆ alkoxy optionally having 1 to 5, preferably 1 to 3, halogen atom(s)(e.g., fluorine, chlorine, bromine, iodine etc.) is mentioned, such asmethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,pentyloxy and hexyloxy, and the like. Specifically, for example,methoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy,hexyloxy and the like are mentioned.

Examples of the aforementioned “optionally halogenated C₁₋₆ alkylthio”include C₁₋₆ alkylthio optionally having 1 to 5, preferably 1 to 3,halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine etc.) such asmethylthio, ethylthio, propylthio, isopropylthio, butylthio,sec-butylthio and tert-butylthio, and the like. Specifically,methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio,pentylthio, hexylthio and the like are mentioned.

In the present specification, the “heterocyclic group” of the“optionally substituted heterocyclic group” is exemplified by amonovalent group and the like obtained by removing optional one hydrogenatom from 5 to 14-membered (monocyclic, bicyclic or tricyclic)heterocycle, preferably (i) 5 to 14-membered (preferably 5 to10-membered) aromatic heterocycle, (ii) 5 to 10-membered non-aromaticheterocycle and (iii) 7 to 10-membered crosslinked heterocycle, having,besides carbon atom, 1 or 2 kind(s) of 1 to 4 hetero atom(s) selectedfrom nitrogen atom, sulfur atom and oxygen atom.

Examples of the above-mentioned “5 to 14-membered (preferably 5 to10-membered) aromatic heterocycle” include aromatic heterocycles such asthiophene, oxazole, triazole, benzo[b]thiophene, benzo[b]furan,benzimidazole, benzoxazole, benzothiazole, benzisothiazole,naphtho[2,3-b]thiophene, furan, pyrrole, imidazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole,purine, 4H-quinolizidine, isoquinoline, quinoline, phthalazine,naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole,β-carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole,phenothiazine, isooxazole, furazan, phenoxazine and the like, and a ringformed by condensation of these rings (preferably monocycle) with 1 toseveral (preferably 1 or 2) aromatic ring(s) (e.g., benzene ring etc.)and the like.

Examples of the above-mentioned “5 to 10-membered non-aromaticheterocycle” include pyrrolidine, imidazoline, pyrazolidine, pyrazoline,piperidine, piperazine, morpholine, thiomorpholine, dioxazole,oxadiazoline, thiadiazoline, triazoline, thiadiazole, dithiazole and thelike.

Examples of the above-mentioned “7 to 10-membered crosslinkedheterocycle” include quinuclidine, 7-azabicyclo[2.2.1]heptane and thelike.

The “heterocyclic group” is preferably 5 to 14-membered (preferably 5 to10-membered) (monocyclic or bicyclic) heterocyclic group having, besidescarbon atom, 1 or 2 kind(s) of preferably 1 to 4 hetero atom(s) selectedfrom nitrogen atom, sulfur atom and oxygen atom. Specific examplesinclude aromatic heterocyclic group such as 2-thienyl, 3-thienyl,2-furyl, 3-furyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4-triazolyl,1,2,3-triazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl,3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl,3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 2-pyrazinyl, 2-pyrimidinyl,4-pyrimidinyl, 3-pyrrolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isooxazolyl, 1-indolyl,2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl,3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl and the like,nonaromatic heterocyclic group such as 1-pyrrolizinyl, 2-pyrrolizinyl,3-pyrrolizinyl, 2-imidazolinyl, 4-imidazolinyl, 2-pyrazolidinyl,3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidyl, 3-piperidyl,4-piperidyl, 1-piperazinyl, 2-piperazinyl, morpholino, thiomorpholinoand the like, and the like.

Of these, 5 or 6-membered heterocyclic group having, 10 besides carbonatom, 1 to 3 hetero atom(s) selected from nitrogen atom, sulfur atom andoxygen atom is more preferable. Specifically, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, pyrazinyl,2-pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isooxazolyl,1-pyrrolizinyl, 2-pyrrolizinyl, 3-pyrrolizinyl, 2-imidazolinyl,4-imidazolinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl,piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperazinyl,2-piperazinyl, morpholino, thiomorpholino and the like are mentioned.

Examples of the “substituent” of the “optionally substitutedheterocyclic group” are similar to the “substituent” of theaforementioned “optionally substituted hydrocarbon group” and the like.

The “heterocyclic group” may have 1 to 5, preferably 1 to 3, forexample, the above-mentioned substituents at substitutable position(s).When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

In the present specification, the “acyl” is exemplified by acyl of theformula: —(C═O)—aR, —(C═O)—OaR, —(C═O)—NaRbR, —(C=S)—NHaR or —SO₂—cRwherein aR is hydrogen atom, optionally substituted hydrocarbon group oroptionally substituted heterocyclic group, bR is hydrogen atom or C₁₋₆alkyl, cR is optionally substituted hydrocarbon group or optionallysubstituted heterocyclic group, and the like.

The “C₁₋₆ alkyl” expressed by R^(a10) and R^(b14) is exemplified bymethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl and the like.

In the present specification, the “optionally substituted amino” isexemplified by (1) amino optionally having 1 or 2 substituent(s) and (2)optionally substituted cyclic amino.

The “substituent” of the “amino optionally having 1 or 2 substituent(s)”of the above-mentioned (1) is exemplified by optionally substitutedhydrocarbon group, optionally substituted heterocyclic group, acyl andthe like.

When the number of the “substituent(s)” of the above-mentioned “aminooptionally having 1 or 2 substituent(s)” is two, the respectivesubstituents may be the same or different.

The “cyclic amino” of the “optionally substituted cyclic amino” of theabove-mentioned (2) is exemplified by 5 to 7-membered non-aromaticcyclic amino having, besides one nitrogen atom and carbon atom, 1 or 2kind(s) of 1 to 4 hetero atom(s) selected from nitrogen atom, sulfuratom and oxygen atom. Specific examples thereof include pyrrolidin-1-yl,piperidino, piperazin-1-yl, morpholino, thiomorpholino,tetrahydroazepin-1-yl, imidazolidin-1-yl, 2,3-dihydro-1H-imidazol-1-yl,tetrahydro-1(2H)-pyrimidinyl, 3,6-dihydro-1(2H)-pyrimidinyl,3,4-dihydro-1(2H)-pyrimidinyl and the like.

The “substituent” of the “optionally substituted cyclic amino” isexemplified by 1 to 3 from C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.),C₆₋₁₄ aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl,3-biphenylyl, 4-biphenylyl, 2-anthryl etc.), C₁₋₆ alkylcarbonyl (e.g.,acetyl, propionyl etc.), 5 to 10-membered aromatic heterocyclic group(e.g., 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 1,2,4-triazolyl,1,2,3-triazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl,3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl,3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 2-pyrazinyl, 2-pyrimidinyl,4-pyrimidinyl, 3-pyrrolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isooxazolyl, 1-indolyl,2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl,3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl etc.) and thelike.

In the present specification, the “substituted amino” is exemplified by(1) amino having 1 or 2 substituent(s) and (2) substituted cyclic amino.As the “substituent” and “cyclic amino”, the “substituent” and “cyclicamino” described in detail in the above-mentioned (1) and (2) are shown.

In the above-mentioned formula, “aromatic group” of the “optionallysubstituted aromatic group” represented by Ar^(c) is exemplified byC₆₋₁₄ aryl, 5 to 14-membered aromatic heterocyclic group and the like.

As the “C₆₋₁₄ aryl”, phenyl, naphthyl (e.g., 1-naphthyl, 2-naphthyletc.), biphenylyl (e.g., 2-biphenylyl, 3-biphenylyl, 4-biphenylyl etc.),anthryl (e.g.,. 2-anthryl etc.) and the like are exemplified. Of these,phenyl is preferable.

The “5 to 14-membered aromatic heterocyclic group” is exemplified by 5to 14-membered (preferably 5 to 10-membered) (monocyclic or bicyclic)aromatic heterocyclic group having, besides carbon atom, 1 or 2 kind(s)of preferably 1 to 4 hetero atom(s) selected from nitrogen atom, sulfuratom and oxygen atom. Specific examples include thienyl (e.g.,2-thienyl, 3-thienyl), furyl (e.g., 2-furyl, 3-furyl), pyridyl (e.g.,2-pyridyl, 3-pyridyl, 4-pyridyl), quinolyl (e.g., 2-quinolyl,3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl), isoquinolyl (e.g.,1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl), pyrazinyl,pyrimidinyl .(e.g., 2-pyrimidinyl, 4-pyrimidinyl), pyrrolyl (e.g.,3-pyrrolyl), imidazolyl (e.g., 2-imidazolyl), pyridazinyl (e.g.,3-pyridazinyl), isothiazolyl (e.g., 3-isothiazolyl), isooxazolyl (e.g.,3-isooxazolyl), indolyl (e.g., 1-indolyl, 2-indolyl, 3-indolyl),benzothiazolyl (e.g., 2-benzothiazolyl), benzothienyl (e.g.,2-benzo[b]thienyl, 3-benzo[b]thienyl), benzofuranyl (e.g.,2-benzo[b]furanyl, 3-benzo[b]furanyl) and the like.

The “substituent” of the aforementioned “optionally substituted C₆₋₁₄aryl” is exemplified by 1 to 5 from halogen, hydroxy, optionallyhalogenated C₁₋₆ alkyl, optionally halogenated C₁₋₆ alkoxy and the like.

The “leaving group” represented by X^(a) is exemplified by halogen(fluoro, chloro, bromo, iodo), alkylsulfonyloxy (e.g., C₁₋₆alkylsulfonyloxy such as methylsulfonyloxy etc.), arylsulfonyloxy (e.g.,C₆₋₁₄ arylsulfonyloxy optionally substituted by C₁₋₆ alkyl, such asp-toluenesulfonyloxy etc.) and the like.

The “substituent” of the “optionally substituted hydroxy” represented byR^(a1) and R^(a2), or R^(b1), R^(b2) and R^(b3) is exemplified by thosesimilar to the “substituent” of the aforementioned “optionallysubstituted hydrocarbon group” and the like.

The “substituent” of the “optionally substituted thiol” represented byR^(a1) and R^(a2), or R^(b1), R^(b2) and R^(b3) is exemplified by thosesimilar to the “substituent” of the aforementioned “optionallysubstituted hydrocarbon group” and the like.

The “substituent” of the “optionally substituted hydroxy” represented byR^(a4), R^(a5), R^(a7) and R^(a8) is exemplified by those similar to the“substituent” of the aforementioned “optionally substituted hydrocarbongroup” and the like.

The “substituent” of the “optionally substituted thiol” represented byR^(a4), R^(a5) R^(a7) and R^(a8) is exemplified by those similar to the“substituent” of the aforementioned “optionally substituted hydrocarbongroup” and the like.

The “aromatic group” of the “optionally substituted aromatic group”represented by R^(a6) is exemplified by C₆₋₁₄ aryl, 5 to 14-memberedheterocyclic group and the like.

Examples of the “C₆₋₁₄ aryl” include, phenyl, 1-naphthyl, 2-naphthyl,2-anthryl and the like. Of these, phenyl is preferable.

The “5 to 14-membered heterocyclic group” is exemplified by 5 to14-membered (preferably 5 to 10-membered) (monocyclic or bicyclic)heterocyclic group having, besides carbon atom, 1 or 2 kind(s) ofpreferably 1 to 4 hetero atom(s) selected from nitrogen atom, sulfuratom and oxygen atom. Specific examples include 2-thienyl, 3-thienyl,2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl,3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl,3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, pyrazinyl, 2-pyrimidinyl,4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl,3-isooxazolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl,2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl,3-benzo[b]furanyl and the like.

The “substituent” of the “optionally substituted aromatic group” isexemplified by those similar to the “substituent” of the aforementioned“optionally substituted hydrocarbon group” and the like.

The “aromatic group” may have 1 to 5, preferably 1 to 3, for example,the above-mentioned substituents at substitutable position(s). When thenumber of the substituents is two or more, the respective substituentsmay be the same or different.

As the halogen represented by R^(a7) and R^(a8), for example, fluoro,chloro, bromo and iodo are mentioned.

As the halogen atom represented by X^(a1), for example, chloro, bromo,iodo and the like are mentioned.

As the alkaline metal atom represented by M^(a), for example, lithium,potassium, sodium and the like are mentioned, and as the alkaline earthmetal, for example, calcium, magnesium and the like are mentioned.

When two of R^(a1), R^(a2) and R^(a3) or two of R^(b1), R^(b2) andR^(b3) form an optionally substituted ring together with the adjacentcarbon atom, the compounds (aII) and (bII) are, for example, representedby the formula:

wherein A ring is an optionally substituted ring, R¹ is R^(a1) orR^(b1), and X is X^(a) or —NH₂.

When three of R^(a1), R^(a2) and R^(a3) or three of R^(b1), R^(b2) andR^(b3) form an optionally substituted ring together with the adjacentcarbon atom, the compounds (aII) and (bII) are represented by theformula:

wherein B ring is an optionally substituted ring and other symbol is asdefined above.

The “ring” of the “optionally substituted ring” formed by two or threeof R^(a1), R^(a2) and R^(a3) and two or three of R^(b1), R^(b2) andR^(b3) is exemplified by 3 to 8-membered homocyclic ring or heterocyclicring and the like.

As the “3 to 8-membered homocyclic ring”, for example, C₃₋₈ cycloalkanesuch as cyclopropane, cyclobutane, cyclopentane, cyclohexane and thelike, C₃₋₈ cycloalkene such as cyclopropene, cyclobutene, cyclopentene,cyclohexene and the like, C₃₋₈ cycloalkyne such as cycloheptyne,cyclooctyne and the like, benzene and the like are mentioned.

As the “3 to 8-membered heterocyclic”, for example, 3 to 8-memberedheterocyclic, such as aziridine, azetidine, morpholine, thiomorpholine,piperazine, piperidine, pyrrolidine, hexamethylenimine,hexamethylenimine, hexahydropyrimidine, pyridine, pyrimidine, oxazole,thiazole, quinoline, benzothiophene and the like are mentioned.

The “substituent” of the “optionally substituted ring” is exemplified bythose similar to the “substituent” of the aforementioned “optionallysubstituted hydrocarbon group” and the like.

The “ring” may have 1 to 5, preferably 1 to 3, for example, theabove-mentioned substituents at substitutable position(s). When thenumber of the substituents is two or more, the respective substituentsmay be the same or different.

The “halogen” represented by X^(b1) and X^(b2) is exemplified by fluoro,chloro, bromo and iodo.

The “substituent” of the “optionally substituted hydroxy” represented byR^(b4), R^(b5), R^(b7) and R^(b8) is exemplified by those similar to the“substituent” of the aforementioned “optionally substituted hydrocarbongroup” and the like.

The “substituent” of the “optionally substituted thiol” represented byR^(b4), R^(b5), R^(b7) and R^(b8) is exemplified by those similar to the“substituent” of the aforementioned “optionally substituted hydrocarbongroup” and the like.

The “alkyl” of the “optionally substituted alkyl” represented by R^(b6)is exemplified by C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) and thelike.

The “substituent” of the “optionally substituted alkyl” is exemplifiedby 1 to 5 from those similar to the “substituent” of the aforementioned“optionally substituted hydrocarbon group” and the like.

The “substituent” of the “optionally substituted phenyl” represented byR^(b6) is exemplified by 1 to 5 from those similar to the “substituent”of the aforementioned “optionally substituted hydrocarbon group” and thelike.

The “aromatic group” of the “optionally substituted aromatic group”represented by R^(b9) is exemplified by C₆₋₁₄ aryl, 5 to 14-memberedheterocyclic group and the like.

The “C₆₋₁₄ aryl” is exemplified by phenyl, 1-naphthyl, 2-naphthyl,2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like. Ofthese, phenyl is preferable.

The “5 to 14-membered heterocyclic group” is exemplified by 5 to14-membered (preferably 5 to 10-membered) (monocyclic or bicyclic)heterocyclic group having, besides carbon atom, 1 or 2 kind(s) ofpreferably 1 to 4 hetero atom(s) selected from nitrogen atom, sulfuratom and oxygen atom. Specific examples include 2-thienyl, 3-thienyl,2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl,3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl,3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, pyrazinyl, 2-pyrimidinyl,4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl,3-isooxazolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl,2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl,3-benzo[b]furanyl and the like.

The “substituent” of the “optionally substituted aromatic group” isexemplified by those similar to the “substituent” of the aforementioned“optionally substituted hydrocarbon group” and the like.

The “aromatic group” may have 1 to 5, preferably 1 to 3, for example,the above-mentioned substituents at substitutable position(s). When thenumber of the substituents is two or more, the respective substituentsmay be the same or different.

The “substituent” represented by R^(b11) is exemplified by those similarto the “substituent” of the aforementioned “optionally substitutedhydrocarbon group” and the like.

The “alkylene” of the “optionally substituted alkylene” represented byR^(b12) is exemplified by C₁₋₁₀ alkylene such as —CH₂—, —(CH₂)₂—,—(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —(CH₂)₇—, —(CH₂)₈— and the like.

The “substituent” of the “optionally substituted alkylene” isexemplified by 1 to 5, preferably 1 to 3, from those similar to the“substituent” of the aforementioned “optionally substituted hydrocarbongroup” and the like. When the number of the substituents is two or more,the respective substituents may be the same or different.

The “alkenylene” of the “optionally substituted alkenylene” representedby R^(b12) is exemplified by C₂₋₁₀ alkenylene such as —CH═CH—,—CH₂—CH═CH—, —CH₂—CH═CH—CH₂—, —CH₂—CH₂—CH═CH—, —CH═CH—CH═CH—,—CH═CH—CH₂—CH₂—CH₂—, —CH═CH—CH═CH—CH₂—CH₂—, —CH═CH—CH═CH—CH═CH—,—CH═CH—CH₂—CH₂—CH₂—CH₂—CH₂—, —CH═CH—CH═CH—CH₂—CH₂—CH₂—,—CH═CH—CH═CH—CH═CH—CH₂—, —CH═CH—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—,—CH═CH—CH═CH—CH₂—CH₂—CH₂—CH₂—, —CH═CH—CH═CH—CH═CH—CH₂—CH₂—,—CH═CH—CH═CH—CH═CH—CH═CH—and the like.

The “substituent” of the “optionally substituted alkenylene” isexemplified by 1 to 5, preferably 1 to 3, from those similar to the“substituent” of the aforementioned “optionally substituted hydrocarbongroup” and the like. When the number of the substituents is two or more,the respective substituents may be the same or different.

The “alkynylene” of the “optionally substituted alkynylene” representedby R^(b12) is exemplified by C₂₋₁₀ alkynylene such as

—C≡C—, —CH₂—C≡C—, —CH₂—C≡C—CH₂—CH₂—

and the like.

The “substituent” of the “optionally substituted alkynylene” isexemplified by 1 to 5, preferably 1 to 3, from those similar to the“substituent” of the aforementioned “optionally substituted hydrocarbongroup” and the like. When the number of the substituents is two or more,the respective substituents may be the same or different.

The “aromatic group” may have 1 to 5, preferably 1 to 3, for example,the above-mentioned substituents at substitutable position(s). When thenumber of the substituents is two or more, the respective substituentsmay be the same or different.

The “lower alkyl” represented by R^(c1), R^(c2), R^(c3), R^(c4) andR^(c5) is explemplified by C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.)and the like.

The “substituent” of the “optionally substituted phenyl”, “optionallysubstituted benzyloxy” and “optionally substituted benzylamino”,represented by R^(c5) is exemplified by 1 to 5, preferably 1 to 3, fromthe “substituent” of the optionally substituted aromatic grouprepresented by Ar^(c) and the like. When the number of the substituentsis two or more, the respective substituents may be the same ordifferent.

The “halogen” represented by X^(c1) and X^(c2) is exemplified byfluorine, chlorine, bromine, iodine and the like.

The “metal” represented by M^(c) is exemplified by alkali metal (e.g.,lithium, sodium, potassium etc.), alkaline earth metal (e.g., magnesium,calcium etc.) and the like.

The reactive derivative of carboxylic acid is exemplified by acid halide(acetyl chloride, acetyl bromide etc.), acid anhydride (acetic anhydrideetc.), and the like.

R^(a1) is preferably hydrogen atom.

It is more preferable that R^(a1) and R^(a2) be hydrogen atoms.

R^(a3) is preferably a group of the formula:

wherein each symbol is as defined above.

More preferably, R^(a4) and R^(a5) are hydrogen atoms.

R^(a6) is preferably phenyl optionally having substituent(s) (preferablyC₁₋₆ alkoxy, particularly tert-butoxy).

m^(a) is preferably 3 or 4.

R^(a7) is preferably hydrogen atom.

R^(a8) is preferably hydrogen atom.

R^(b1) is preferably hydrogen atom.

It is more preferable that R^(b1) and R^(b2) be hydrogen atoms.

R^(b3) is preferably a group of the formula:

wherein each symbol is as defined above.

More preferably, R^(b7) and R^(b8) are hydrogen atoms.

R^(b9) is preferably phenyl optionally having substituent(s) (preferablyC₁₋₆ alkoxy).

m^(b) is preferably 3.

R^(b4) and R^(b5) are preferably hydrogen atoms.

R^(b6) is preferably phenyl optionally having substituent(s) (preferablyalkyl).

R^(b10) is preferably optionally substituted hydrocarbon group(preferably alkyl), more preferably C₁₋₃ alkyl.

n^(b)is preferably 0.

R^(b12) is preferably optionally substituted alkylene, more preferablytrimethylene.

Ar^(c) is preferably optionally substituted phenyl, more preferably4-trifluoromethylphenyl.

R^(c1) is preferably hydrogen atom.

R^(c2) is preferably hydrogen atom.

R^(c3) is preferably hydrogen atom.

R^(c4) is preferably hydrogen atom.

Y^(c) is preferably carbon atom.

M^(c) is preferably alkali metal (e.g., lithium, sodium, potassiumetc.).

R^(c5) is preferably lower alkyl, more preferably methyl.

n^(c) is preferably 4.

The compound (cIV) is a novel compound, which is specificallyexemplified by4-(acetoxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazoleand a salt thereof.

The salts of the compounds represented by the formulas (aIa), (aIb),(bI), (cI)-(cVII), (cIa), (cVa), (cVIIa) and the like in thespecification are preferably pharmacologically acceptable salts, whichare exemplified by salts with inorganic acids, salts with organic acids,salts with inorganic base, salts with organic base and the like.

Examples of the salts with inorganic acid include salts withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid and the like.

Examples of the salts with organic acid include salts with formic acid,acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaricacid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid andthe like.

Examples of the salts with inorganic base include alkali metal salt suchas sodium, potassium salt and the like; alkaline earth metal salt suchas calcium salt, magnesium salt and the like; ammonium salt and thelike.

Examples of the salts with organic base include salts withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,N,N′-dibenzylethylenediamine and the like.

The production methods of compounds (aIa) and (aIb) useful as anintermediate for a 1-substituted-1,2,3-triazole compound having aninhibitory action on tyrosine kinases (especially HER2) are shown in thefollowing.

When the compound (aII) and compound (aIII) are on the market,commercially available products thereof may be used as they are, orcompound (aII) and compound (aIII) may be produced according to a methodknown per se, a method analogous thereto, and the like.

wherein each symbol is as defined above.

Reaction a1

The compound (aII) and compound (aIII) are reacted in secondary ortertiary alcohol in the presence of a base to give compound (aIa) or(aIb).

The amount of use of compound (aIII) is about 0.1-10 mol, preferablyabout 0.5-3.0 mol, per 1 mol of compound (aII).

The amount of use of the base is about 0.1-10 mol, preferably about0.5-3.0 mol, per 1 mol of compound (aII).

Examples of the “base” include hydride of alkali metal or alkaline earthmetal (e.g., lithium hydride, sodium hydride, potassium hydride, calciumhydride etc.), amide of alkali metal or alkaline earth metal (e.g.,lithium amide, sodium amide, lithium diisopropylamade, lithiumdicyclohexylamide, lithium hexamethyl disilazide, sodium hexamethyldisilazide, potassium hexamethyl disilazide etc.), hydroxide of alkalimetal or alkaline earth metal (e.g., sodium hydroxide, potassiumhydroxide, lithium hydroxide, calcium hydroxide etc.), metal hydrocarbon(e.g., butyllithium, tert-butyllithium etc.), lower alkoxide of alkalimetal or alkaline earth metal (e.g., sodium methoxide, sodium ethoxide,potassium tert-butoxide etc.), carbonate of alkali metal or alkalineearth metal (e.g., sodium hydrogen carbonate, sodium carbonate,potassium carbonate etc.), organic bases [amines (e.g., triethylamine,diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine, DBU(1,8-diazabicyclo[5.4.0]undec-7-ene), DBN(1,5-diazabicyclo[4.3.0]non-5-ene) etc.), organic base of basicheterocyclic compound (e.g., pyridine, imidazole, 2,6-lutidine etc.)etc.], and the like. Of these, hydroxide of alkali metal or alkalineearth metal is preferable.

Examples of the “secondary or tertiary alcohol” include secondaryalcohol such as isopropyl alcohol, 2-butanol etc., tertiary alcohol suchas tert-butanol, 2,-methyl-2-butanol etc., and the like. Of these,tertiary alcohol is preferable.

This reaction may be carried out in a solvent inert to the reaction,besides secondary or tertiary alcohol. Examples of the “inert solvent”include halogenated hydrocarbons (e.g., dichloromethane, chloroform,1,2-dichloroethane, carbon tetrachloride etc.), aromatic hydrocarbons(e.g., benzene, toluene, xylene, chlorobenzene etc.), ethers (e.g.,diethyl ether, diisopropy ether, tert-butylmethyl ether, diphenyl ether,tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme etc.), aliphatichydrocarbons (e.g., hexane, pentane, cyclohexane etc.), amides (e.g.,N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone,hexamethylphosphoric triamide etc.), sulfoxides (e.g., dimethylsulfoxide etc.), primary alcohols (e.g., methanol, ethanol), nitrites(e.g., acetonitrile, propionitrile etc.), water, a mixture of two ormore thereof and the like.

This reaction is carried out in the presence of an inorganic salt (e.g.,halogenated alkali metal salt such as sodium iodide, sodium bromide,potassium iodide, potassium bromide etc.), where necessary.

The reaction temperature is generally from about 0° C. to 150° C.,preferably from about 20° C. to 130° C. The reaction time is generallyabout 0.5 hour to 100 hours, preferably about 1 hour to 20 hours.

The compound (aIa) or (aIb) thus obtained can be isolated and purifiedfrom a reaction mixture by a known method, such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phase transfer, chromatography andthe like.

For example, a method comprising addition of an acid after theabove-mentioned reaction, and isolation and purification to give a saltof compound (aIa) or (aIb) is preferably mentioned. Examples of the“acid” include mineral acids such as hydrochloric acid, hydrobromicacid, sulfuric acid etc., organic acids such as acetic acid,trifluoroacetic acid, tartaric acid, maleic acid, citric acid,methanesulfonic acid, p-toluenesulfonic acid etc., and the like. Theamount of use of the “acid” is about 0.3-5.0 mol, preferably about0.8-1.5 mol, per 1 mol of compound (aII).

Reaction a2

The compound (aII) and compound (aIII) are reacted in the absence of abase to give compound (aIa) or (aIb).

The amount of use of compound (aIII) is about 0.1-100 mol, preferablyabout 0.5-5 mol, per 1 mol of compound (aII).

This reaction is carried out in the presence of a solvent inert to thereaction. Examples of the “inert solvent” include halogenatedhydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane,carbon tetrachloride etc.), aromatic hydrocarbons (e.g., benzene,toluene, xylene, chlorobenzene etc.), ethers (e.g., diglyme, diethylether, diisopropy ether, tert-butylmethyl ether, diphenyl ether,tetrahydrofuran, dioxane, 1,2-dimethoxyethane etc.), aliphatichydrocarbons (e.g., hexane, pentane, cyclohexane etc.), amides (e.g.,N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone,hexamethylphosphoric triamide etc.), sulfoxides (e.g., dimethylsulfoxide etc.), alcohols (e.g., methanol, ethanol, isopropyl alcohol,2-butanol, tert-butanol, 2-methyl-2-butanol etc.), nitriles (e.g.,acetonitrile, propionitrile etc.), water, a mixture of two or morethereof and the like. Of these, toluene, diglyme, N,N-dimethylformamide,dimethyl sulfoxide, 2-butanol, 2-methyl-2-butanol and the like arepreferable.

Where necessary, this reaction is carried out in the presence of aninorganic salt (e.g., halogenated alkali metal salt such as sodiumiodide, sodium bromide, potassium iodide, potassium bromide etc.).

The reaction temperature is generally from about 0° C. to 150° C.,preferably from about 20° C. to 130° C. The reaction time is generallyabout 0.5 hour to 100 hours, preferably about 1 hour to 50 hours.

The compound (aIa) or (aIb) thus obtained can be isolated and purifiedfrom a reaction mixture by a known method, such as concentration,concentration under reduced pressure, solvent extraction,crystallization, recrystallization, phase transfer, chromatography andthe like.

For example, a method comprising addition of an acid after theabove-mentioned reaction, and isolation and purification to give a saltof compound (aIa) or (aIb) is preferably mentioned. Examples of the“acid” include mineral acids such as hydrochloric acid, hydrobromicacid, sulfuric acid etc., organic acids such as acetic acid,trifluoroacetic acid, tartaric acid, maleic acid, citric acid,methanesulfonic acid, p-toluenesulfonic acid etc., and the like. Theamount of use of the “acid” is about 0.3-5.0 mol, preferably about0.8-1.5 mol, per 1 mol of compound (aII).

Of the compounds (aIa) and (aIb), a salt of the compound of the formula

is novel. Examples of the “salt” include those similar to the salt of acompound of the above-mentioned formula (aIa). Of those, acid additionsalts such as hydrochloride, methanesulfonic acid salt and the like arepreferable.

Of the compounds (aIa) and (aIb), a compound of the formula (aIe) and asalt thereof are novel. Examples of the salt include those similar tothe salt of a compound of the above-mentioned formula (aIa).

By deprotection of compound (ale), a compound of the formula:

and a salt thereof can be produced. Examples of the salt include thosesimilar to the salt of a compound of the above-mentioned formula (aIa).This deprotection can be carried out under mild conditions from amongthe general means of deprotecting protected hydroxy group, and isindustrially advantageous. For example, compound (aIe) is reacted in thepresence of an acid to remove t-butyl, which is a hydroxy protectinggroup according to a conventional method for deprotection. Examples ofthe “acid” include organic acids such as acetic acid, trifluoroaceticacid, trichloroacetic acid, tartaric acid, maleic acid, citric acid,methanesulfonic acid, toluenesulfonic acid and the like, and mineralacids such as sulfuric acid, hydrochloric acid, hydrobromic acid,chloric acid, perchloric acid, bromic acid, perbromic acid, iodic acid,periodic acid and the like. The solvent may be or may not be used. Theacid may be or may not be diluted. When it is to be diluted, it ispreferably diluted to 0.01 N-5 N. The reaction temperature is generallyfrom 0° C. to 100° C., preferably from 20° C. to 70° C. The reactiontime is generally about 0.1 hour to 5 hours, preferably about 0.1 hourto 2 hours.

The compound (aIe) can be produced by reacting, from among the compounds(aII), a compound [compound (aIIa)] wherein R^(a1) and R^(a2) are bothhydrogen atoms and R^(a3) is 3-[4-(tert-butoxyphenyl)]-propyl andtriazole.

The compound (aIIa) can be produced by, for example, reacting compound(aII′) and compound (aa), (ab), (ac) or (ad) under basic conditions.That is, by reacting compound (aII′) and compound (aa) or (ab), acompound wherein X^(a′) is halogen can be produced from among thecompounds (aIIa), and by reacting compound (aII′) and compound (ac), acompound wherein X^(a′) is OSO₂R^(a) can be produced from among thecompounds (aIIa), and by reacting compound (aII′) and compound (ad), acompound wherein X^(a′) is OCOR^(a) can be produced from among thecompounds (aIIa). These reactions are all carried out under basicconditions. When a compound wherein M^(a) is alkaline metal atom oralkaline earth metal atom is used as compound (aII′), a base does notneed to be added, because they are basic, but when a compound whereinM^(a) is hydrogen atom is used as compound (aII′), a base is generallyadded to the reaction mixture. Examples of the preferable “base” includetertiary amines such as trimethylamine, triethylamine,1,8-diazabicyclo[5.4.0]-7-undecene etc., heterocyclic aromatic organicbases such as pyridine, picoline etc. and the like.

When compound (aII′) and compound (aa) or (ab) are reacted, the reactiongenerally proceeds in a solvent inert to the reaction under basicconditions. Alternatively, the “base” may be used as a solvent. Examplesof the “solvent” include halogenated hydrocarbons such asdichloromethane, dichloroethane and the like, aromatic hydrocarbons suchas benzene, toluene, xylene and the like, ethers such as diethyl ether,diisopropy ether, tert-butylmethyl ether, tetrahydrofuran and the like,nitrites such as acetonitrile, propionitrile, isopropionitrile and thelike, and esters such as ethyl acetate, isopropyl acetate and the like.The reaction temperature is generally from 0° C. to 100° C., preferably10° C. to 70° C.

The compound (aII′) and compound (ac) or (ad) can be reacted accordingto a conventional method, which proceeds in an organic solvent generallyinert to the reaction under basic conditions. Alternatively, the “base”may be used as a solvent. Examples of the “organic solvent inert to thereaction” include halogenated hydrocarbons such as dichloromethane,dichloroethane and the like, aromatic hydrocarbons such as benzene,toluene, xylene and the like, ethers such as diethyl ether, diisopropyether, tert-butylmethyl ether, tetrahydrofuran and the like, nitritessuch as acetonitrile, propionitrile, isopropionitrile and the like,esters such as ethyl acetate, isopropyl acetate and the like, and thelike. The reaction is generally carried out by cooling a solutioncontaining compound (aII′) to a temperature of not more than 10° C.,adding dropwise compound (aa) thereto with stirring and reacting themixture at 5-20° C. for 10 min-6 hours.

Of the compounds (aIIa), a compound wherein X^(a′) is OSO₂R^(a) orOCOR^(a) is further reacted with halogen compound to produce a compoundwherein X^(a′) is halogen from among the compounds (aIIa).

By reacting halogen compound with sulfonyloxy compound [compound whereinX^(a′) is OSO₂R^(a) in the formula (aIIa)] produced by reacting theabove-mentioned (aII′) and compound (ac), a compound wherein X^(a′) ishalogen in the formula (aIIa) can be produced. Generally, theabove-mentioned sulfonyloxy compound is reacted with halogen compound[e.g., alkali halide (e.g., sodium chloride, potassium chloride, sodiumbromide, potassium bromide, sodium iodide, potassium iodide etc.),pyridinium halide (pyridinium chloride, pyridinium bromide, pyridiniumiodide etc.), hydrogen halide (e.g., hydrochloric acid, hydrobromicacid, hydriodic acid etc.), hydrogen halide salt of tertiary amine(e.g., trimethylamine hydrochloride, trimethylamine hydrobromide,triethylamine hydrochloride, triethylamine hydrobromide etc.) and thelike] in a solvent in the presence of a base [inorganic base (e.g.,alkali metal such as sodium, potassium etc.; alkaline earth metal suchas calcium, magnesium etc.; hydroxide such as ammonium etc.) or anorganic base (e.g., trimethylamine, triethylamine, pyridine, picolineetc.)]. Alternatively, by reacting compound (aII′) and a compound,wherein X is OSO₂R^(a) from among the compounds (ac), and then reactingthe resulting compound with halogen compound, compound (aIIa) whereinX^(a′) is halogen can be also produced. The solvent only needs to beinert. Examples thereof include chain or cyclic ethers such as diethylether, diisopropy ether, tert-butylmethyl ether, tetrahydrofuran and thelike, chain alcohols having 1 to 5 carbon atoms, such as methanol,ethanol, isopropyl alcohol and the like, ketones such as acetone,2-butanone, 2-pentanone, 3-pentanone and the like, ethers such asdiethyl ether, diisopropy ether, tert-butylmethyl ether, tetrahydrofuranand the like, nitrites such as acetonitrile, propionitrile,isopropionitrile and the like, esters such as ethyl acetate, isopropylacetate and the like, amides such as N,N-dimethylacetamide,N,N-dimethylacetamide, N-methylpyrrolidone and the like, and the like.Alternatively, the “base” may be used alone as a solvent. The reactiontemperature is from room temperature to the boiling point of thesolvent, preferably from 25° C. to the boiling point of the solvent. Thereaction can be generally terminated upon confirmation of decrease inthe starting materials by a typical analytical method.

The compound (aIIa) obtained in this way is novel.

Of the compounds (aIa) and (aIb), for example, a compound of the formula

wherein R^(a1a), R^(a2a), R^(a4a) and R^(a5a) are each a hydrogen atom,R^(a6a) is phenyl having (i) optionally substituted hydroxy or (ii)optionally substituted thiol as a substituent, and other symbols are asdefined above, and a salt thereof can be converted to a1-substituted-1,2,3-triazole compound useful as a pharmaceutical agentand the like, according to a method known per se, such as a methoddescribed in JP-A-11-60571 or a method analogous thereto.

The “optionally substituted hydroxy” of the “phenyl substituted byoptionally substituted hydroxy” represented by R^(a6a) is exemplified bythose similar to the aforementioned “optionally substituted hydroxy”represented by R^(a4) or R^(a5).

The “optionally substituted thiol” of the “phenyl substituted byoptionally substituted thiol” represented by R^(a6a) is exemplified bythose similar to the aforementioned “optionally substituted thiol”represented by R^(a4), R^(a5), R^(a7) or R^(a8).

For example, compound (aIc) or (aId) is subjected to deprotection knownper se, where necessary, then reacted with a compound of the formula

R^(a12)—(CH₂)_(qa)—W^(a)

wherein R^(a12) is an optionally substituted aromatic heterocyclicgroup, qa is an integer of 1 to 5, and W^(a) is a leaving group, or asalt thereof [hereinafter to be briefly referred to as compound (aIV)]to give a compound of the formula

wherein X^(a1) is an oxygen atom or a sulfur atom, and other symbols areas defined above, or a salt thereof.

When the compound (aIV) is on the market, a commercially availableproduct thereof may be used as it is, or compound (aIV) may be producedaccording to a method known per se, a method analogous thereto, and thelike.

The “leaving group” represented by W^(a) is exemplified by those similarto the “leaving group” represented by X^(a) and the like.

The “aromatic heterocyclic group” of the “optionally substitutedaromatic heterocyclic group” represented by R^(a12) is exemplified by 5to 14-membered (preferably 5 to 10-membered) (monocyclic or bicyclic)heterocyclic group, having, besides carbon atom, 1 or 2 kind(s) ofpreferably 1 to 4 hetero atom(s) selected from nitrogen atom, sulfuratom and oxygen atom. Examples thereof include 2-thienyl, 3-thienyl,2-furyl, 3-furyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4-triazolyl,1,2,3-triazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl,3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl,3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 2-pyrazinyl, 2-pyrimidinyl,4-pyrimidinyl, 3-pyrrolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isooxazolyl, 1-indolyl,2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl,3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl and the like.Preferred is oxazolyl such as 2-oxazolyl, 4-oxazolyl, 5-oxazolyl and thelike.

The “substituent” of the “optionally substituted aromatic heterocyclicgroup” represented by R^(a12) is exemplified by 1 to 5 from “optionallysubstituted hydroxy”, “optionally substituted thiol”, “optionallysubstituted amino”, “optionally substituted hydrocarbon group”,“optionally substituted heterocyclic group” and “acyl” represented byR^(a4) and R^(a5). Of these, optionally substituted hydrocarbon group ispreferable andC₂₋₆ alkenylene substituted by optionally substitutedC₆₋₁₄ aryl is more preferable.

Reaction b1

wherein each symbol is as defined above.

The compound (bII) and compound (bIII) are reacted and the reactionmixture is treated with a base to give compound (bI).

When the compound (bII) is on the market, a commercially availableproduct thereof may be used as it is, or compound (bII) may be producedaccording to a method known per se, a method analogous thereto, themethod of Reaction B to be mentioned later and the like.

When the compound (bIII) is on the market, a commercially availableproduct thereof may be used as it is, or compound (bIII) may be producedaccording to a method known per se, a method analogous thereto, and thelike.

The amount of use of compound (bIII) is about 0.1-10 mol, preferablyabout 0.5-3.0 mol, per 1 mol of compound (bII).

The reaction of compound (bII) and compound (bIII) is preferably carriedout in a solvent inert to the reaction. Examples of the “inert solvent”include halogenated hydrocarbons (e.g., dichloromethane, chloroform,1,2-dichloroethane, carbon tetrachloride etc.), aromatic hydrocarbons(e.g., benzene, toluene, xylene, chlorobenzene etc.), ethers (e.g.,diethyl ether, diisopropy ether, tert-butylmethyl ether, diphenyl ether,tetrahydrofuran, dioxane, 1,2-dimethoxyethane etc.), aliphatichydrocarbons (e.g., hexane, pentane, cyclohexane etc.), alcohols (e.g.,methanol, ethanol, isopropylalcohol, 2-butanol, tert-butanol,2-methyl-2-butanol etc.), amides (e.g., N,N-dimethylformamide,N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, hexamethylphosphorictriamide etc.), sulfoxides (e.g., dimethyl sulfoxide etc.), nitriles(e.g., acetonitrile, propionitrile etc.), water, a mixture of two ormore thereof and the like. Of these, methanol is preferable.

The reaction temperature is generally from about 0° C. to 150° C.,preferably from about 10 to 80° C. The reaction time is generally fromabout 0.2 hour to 20 hours, preferably from about 0.5 hour to 3 hours.

Then the reaction mixture is treated with a base to give compound (bI).

The treatment with a base generally includes mixing the reaction mixturewith a base, or concentration of the reaction mixture followed by mixingof the concentrate with a base.

The amount of use of the base is about 0.1-500 mol, preferably about1-200 mol, per 1 mol of compound (bII).

Examples of the “base” include hydride of alkali metal or alkaline earthmetal (e.g., lithium hydride, sodium hydride, potassium hydride, calciumhydride etc.), amide of alkali metal or alkaline earth metal (e.g.,lithium amide, sodium amide, lithium diisopropylamide, lithiumdicyclohexylamide, lithium hexamethyl disilazide, sodium hexamethyldisilazide, potassium hexamethyl disilazide etc.), lower alkoxide ofalkali metal or alkaline earth metal (e.g., sodium methoxide, sodiumethoxide, potassium tert-butoxide etc.), carbonate of alkali metal oralkaline earth metal (e.g., sodium carbonate, potassium carbonate etc.),hydrogencarbonate of alkali metal or alkaline earth metal (e.g., sodiumhydrogen carbonate, potassium hydrogen carbonate etc.), hydroxide ofalkali metal or alkaline earth metal (e.g., sodium hydroxide, potassiumhydroxide, lithium hydroxide, calcium hydroxide), metal hydrocarbon(n-butyl lithium, tert-butyl lithium), organic bases [amines (e.g.,triethylamine, diisopropylethylamine, N-methylmorpholine,dimethylaminopyridine, DBU (1,8-diazabicyclo [5.4.0]undec-7-ene), DBN(1,5-diazabicyclo[4.3.0]non-5-ene) etc.), organic base of basicheterocyclic compound (e.g., pyridine, imidazole, 2,6-lutidine etc.)etc.], and the like. Of these, hydrogencarbonate of alkali metal oralkaline earth metal is preferable. More preferred is sodium hydrogencarbonate.

The base may be used as it is or used after dissolving in an inertsolvent. Examples of the “inert solvent” include the aforementioned“inert solvent”.

The temperature for treatment with a base is generally about 0-70° C.,preferably about 10-40° C. The reaction mixture may be left standing orstirred or immediately subjected to isolation and purification ofcompound (bI) after addition of a base. When the reaction mixture isstood or stirred, the time of standing or stirring is generally about0.01-5 hour, preferably about 0.1-2 hours.

The compound (bI) thus obtained can be isolated and purified from areaction mixture by a known method, such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, phase transfer, chromatography and the like.

Of the compounds (bI), for example, a compound of the formula

wherein R^(b1a), R^(b2a), R^(b7a) and R^(b8a) are each a hydrogen atom,R^(b9a) is phenyl having (i) optionally substituted hydroxy or (ii)optionally substituted thiol as substituent(s), and other symbols are asdefined above, and a salt thereof can be converted to a1-substituted-1,2,3-triazole compound useful as a pharmaceutical agentand the like, according to a method known per se, such as a methoddescribed in JP-A-11-60571 or a method analogous thereto.

The “optionally substituted hydroxy” of the “phenyl substituted byoptionally substituted hydroxy” represented by R^(b9a) is exemplified bythose similar to the aforementioned “optionally substituted hydroxy”represented by R^(b4) or R^(b5) and the like.

The “optionally substituted thiol” of the “phenyl substituted byoptionally substituted thiol” represented by R^(b9a) is exemplified bythose similar to the aforementioned “optionally substituted thiol”represented by R^(b4), R^(b5), R^(b8) and the like.

For example, compound (bIa) is subjected to deprotection known per se,where necessary, and reacted with a compound of the formula

R^(b16)—(CH₂)_(qb)—W^(b)

wherein R^(b16) is an optionally substituted aromatic heterocyclicgroup, qb is an integer of 1 to 5, and W^(b) is a leaving group, or asalt thereof [hereinafter to be briefly referred to as compound (bIX)]to give a compound of the formula

wherein X^(b) is an oxygen atom or sulfur atom, and other symbols are asdefined above, or a salt thereof.

When the compound (bIX) is on the market, a commercially availableproduct thereof may be used as it is, or compound (bIX) may be producedaccording to a method known per se, a method analogous thereto, and thelike.

Examples of the “leaving group” represented by W^(b) include halogen(fluoro, chloro, bromo, iodo), alkylsulfonyloxy (e.g., C₁₋₆alkylsulfonyloxy such as methylsulfonyloxy etc.), arylsulfonyloxy (e.g.,C₆₋₁₄ arylsulfonyloxy optionally substituted by C₁₋₆ alkyl, such asp-toluenesulfonyloxy etc.) and the like.

The “aromatic heterocyclic group” of the “optionally substitutedaromatic heterocyclic group” represented by R^(b16) is exemplified by 5to 14-membered (preferably 5 to 10-membered) (monocyclic or bicyclic)heterocyclic group having, besides carbon atom, 1 or 2 kind(s) ofpreferably 1 to 4 hetero atom(s) selected from nitrogen atom, sulfuratom and oxygen atom and the like. Specific examples thereof include2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-oxazolyl, 4-oxazolyl,5-oxazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl,1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 2-pyrazinyl,2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 1-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, 3-pyridazinyl, 3-isothiazolyl,3-isooxazolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl,2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl,3-benzo[b]furanyl and the like. Preferred is oxazolyl such as2-oxazolyl, 4-oxazolyl, 5-oxazolyl and the like.

The “substituent” of the “optionally substituted aromatic heterocyclicgroup” represented by R^(b16) is exemplified by 1 to 5 from theaforementioned “optionally substituted hydroxy”, “optionally substitutedthiol”, “optionally substituted amino”, “optionally substitutedhydrocarbon group”, “optionally substituted heterocyclic group”, “acyl”and the like represented by R^(b4) or R^(b5). Of these, optionallysubstituted hydrocarbon group is preferable, and C₂₋₆ alkenylenesubstituted by optionally substituted C₆₋₁₄ aryl is more preferable.

The amine compound such as compound (bII) can be also produced accordingto the method of the following Reaction b2.

Reaction b2

wherein each symbol is as defined above.

The compound (bIV) and compound (bV) are reacted to give compound (bVI),which is then subjected to reduction to give the objective aminecompound [compound (bVII)].

In the reaction of compound (bIV) and compound (bV), the amount of useof compound (bV) is about 0.1-10 mol, preferably about 1-2 mol, per 1mol of compound (bIV).

The reaction of compound (bIV) and compound (bV) is carried out in thepresence of an acid on demand.

Examples of the “acid” include Lewis acid (e.g., anhydrous aluminumchloride, zinc chloride, tin chloride etc.), and strong acid (e.g.,sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acidetc.).

The amount of use of the “acid” is about 0.1-100 mol, preferably about1-10 mol, per 1 mol of compound (bIV).

The reaction of compound (bIV) and compound (bV) is carried out withoutsolvent or in a solvent inert to the reaction. Examples of the “inertsolvent” include halogenated hydrocarbons (e.g., dichloromethane,chloroform, 1,2-dichloroethane, carbon tetrachloride etc.), aromatichydrocarbons (e.g., benzene, toluene, xylene, chlorobenzene etc.),ethers (e.g., diethyl ether, diisopropy ether, tert-butylmethyl ether,diphenyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyehtane etc.),aliphatic hydrocarbons (e.g., hexane, pentane, cyclohexane etc.), amides(e.g., N,N-dimethylformamide, N,N-dimethylacetamide,1-methyl-2-pyrrolidone, hexamethylphosphoric triamide etc.), sulfoxides(e.g., dimethyl sulfoxide etc.), nitriles (e.g., acetonitrile,propionitrile etc.) and a mixture of two or more of these. Preferably,the reaction is carried out without solvent.

The reaction temperature is generally from about −100° C. to 200° C.,preferably from about 0° C. to 100° C. The reaction time is generallyabout 0.1 hour to 50 hours, preferably about 0.5 hour to 10 hours.

The compound (bVI) thus obtained can be used in the next reaction as areaction mixture or as a crude product. It is also possible to isolatethe compound from the reaction mixture according to a conventionalmethod and the compound can be easily purified by a separation meanssuch as recrystallization, distillation, chromatography and the like.

Of the compounds (bVI), trifluoromethanesulfonic acid salt of thecompound of the formula

wherein R^(b12) is trimethylene and other symbols are as defined above,is novel.

The compound (bVI) is reduced to give compound (bVII).

The reduction can be carried out according to catalytic reduction knownper se. The compound (bVI) and a catalytic amount of a metal catalyst(e.g., Raney-nickel, platinum oxide, metal palladium, palladium-carbonetc.) are reacted in an inert solvent under hydrogen pressure of 0-100atm, preferably 0-5 atm.

Examples of the “inert solvent” include halogenated hydrocarbons (e.g.,dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachlorideetc.), aromatic hydrocarbons (e.g., benzene, toluene, xylene,chlorobenzene etc.), ethers (e.g., diethyl ether, diisopropy ether,tert-butylmethyl ether, diphenyl ether, tetrahydrofuran, dioxane,1,2-dimethoxyethane etc.), aliphatic hydrocarbons (e.g., hexane,pentane, cyclohexane etc.), alcohols (e.g., methanol, ethanol,isopropylalcohol, 2-butanol, tert-butanol, 2-methyl-2-butanol etc.),amides (e.g., N,N-dimethylformamide, N,N-dimethylacetamide,1-methyl-2-pyrrolidone, hexamethylphosphoric triamide etc.), sulfoxides(e.g., dimethyl sulfoxide etc.), nitriles (e.g., acetonitrile,propionitrile etc.), organic acids (e.g., acetic acid etc.), water, amixture of two or more thereof and the like. Of these, ethers, aceticacid and the like are preferable.

The reaction temperature is from 0° C. to 100° C., preferably from 20°C. to 70° C. The reaction time is generally about 0.5 hour to 100 hours,preferably about 1 hour to 50 hours.

The compound (bVII) thus obtained can be used in the next reaction as areaction mixture or as a crude product. It is also possible to isolatethe compound from the reaction mixture according to a conventionalmethod and the compound can be easily purified by a separation meanssuch as recrystallization, distillation, chromatography and the like.

The compound (bVII) can be converted to compound (bVIII) useful as anintermediate for a 1-substituted-1,2,3-triazole compound having atyrosine kinase (especially, HER2) inhibitory action, by reacting thecompound with compound (bIII).

Reaction b3

wherein each symbol is as defined above.

The reaction of compound (bVII) and compound (bIII) can be carried outunder the reaction conditions detailed in the aforementioned reactionb1.

The compound (bVIII) thus obtained can be isolated and purified from areaction mixture by a known method, such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, phase transfer, chromatography and the like.

Of the compounds (bVIII), for example, a compound of the formula

wherein R^(b12a) is C₁₋₁₀ alkylene and other symbols are as definedabove, or a salt thereof can be converted to a1-substituted-1,2,3-triazole compound useful as a pharmaceutical agentand the like, according to a method known per se, such as a methoddescribed in JP-A-11-60571 or a method analogous thereto.

For example, compound (bVIIIa) is subjected to deprotection reactionknown per se, and reacted with compound (bIX) to give a compound of theformula

wherein each symbol is as defined above, or a salt thereof.

The production method of compound (cIV) useful as an intermediate forthe production of an oxazole compound (cVII) having a tyrosine kinase(especially, HER2) inhibitory action is described in the following.

Reaction c1

A reaction mixture of compound (cI) and compound (cII) is reacted withcompound (cIII) to give compound (cIV).

When the compound (cI) is on the market, a commercially availableproduct thereof may be used as it is, or compound (cI) may be producedaccording to a method known per se, a method analogous thereto, and thelike.

When the compound (cII) is on the market, a commercially availableproduct thereof may be used as it is, or compound (cII) may be producedaccording to a method known per se, a method analogous thereto, and thelike.

When the compound (cIII) is on the market, a commercially availableproduct thereof may be used as it is, or compound (cIII) may be producedaccording to a method known per se, a method analogous thereto, and thelike.

Preferably, the reaction of compound (cI) and compound (cII) is carriedout in the presence of an acid or a base and, where desired, in asolvent inert to the reaction.

The amount of use of compound (cII) is about 0.1-10 equivalents,preferably about 1-3 equivalents, relative to compound (cI).

The amount of use of acid is about 0.01-10 equivalents, preferably about0.01-3 equivalents, relative to compound (cI).

The amount of use of base is about 0.01-10 equivalents, preferably about0.01-3 equivalents, relative to compound (cI).

Examples of the “acid” include hydrochloric acid, sulfuric acid,trifluoromethanesulfonic acid, trifluoroacetic acid and the like.

Examples of the “base” include carbonate of alkali metal or alkalineearth metal (e.g., sodium carbonate, potassium carbonate etc.),hydrogencarbonate of alkali metal or alkaline earth metal (e.g., sodiumhydrogen carbonate, potassium hydrogen carbonate etc.), hydroxide ofalkali metal or alkaline earth metal (e.g., sodium hydroxide, potassiumhydroxide, lithium hydroxide, calcium hydroxide) and the like.

Examples of the “inert solvent” include aliphatic hydrocarbons (e.g.,hexane, pentane, cyclohexane etc.), aromatic hydrocarbons (e.g.,benzene, toluene, xylene, chlorobenzene etc.), ethers (e.g., diethylether, diisopropy ether, tert-butylmethyl ether, diphenyl ether,tetrahydrofuran, dioxane, 1,2-dimethoxyethane etc.), halogenatedhydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane,carbon tetrachloride etc.), esters (e.g., ethyl acetate etc.), ketones(e.g., acetone, methyl ethyl ketone etc.), nitriles (e.g., acetonitrile,propionitrile etc.), sulfoxides (e.g., dimethyl sulfoxide etc.), amides(e.g., N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone, hexamethylphosphoric triamide etc.), alcohols(e.g., methanol, ethanol, isopropyl alcohol, 2-butanol, tert-butanol,2-methyl-2-butanol etc.), water, a mixture of two or more thereof andthe like. Of these, aromatic hydrocarbons such as toluene, xylene andthe like are preferable.

The reaction temperature is generally from about 0° C. to 200° C.,preferably from about 20° C. to 160° C. The reaction time is generallyabout 1 hour to 48 hours, preferably about 1 hour to 24 hours.

The reaction of compound (cIII) and a reaction mixture of compound (cI)and compound (cII) is preferably carried out in the presence of a baseand(or) a phase transfer catalyst and in a solvent inert to thereaction, where desired.

The compound (cIII) may be an anhydride or hydrate.

The amount of use of compound (cIII) is about 0.1-10 equivalents,preferably about 1-8 equivalents, relative to compound (cI).

The amount of use of base is about 0.1-10 equivalents, preferably about1-8 equivalents, relative to compound (cI).

The amount of use of the phase transfer catalyst is about 0.01-1equivalent, preferably about 0.01-0.3 equivalent, relative to compound(cI).

Examples of the “base” include carbonate of alkali metal or alkalineearth metal (e.g., sodium carbonate, potassium carbonate etc.),hydrogencarbonate of alkali metal or alkaline earth metal (e.g., sodiumhydrogen carbonate, potassium hydrogen carbonate etc.), hydroxide ofalkali metal or alkaline earth metal (e.g., sodium hydroxide, potassiumhydroxide, lithium hydroxide, calcium hydroxide) and the like.

Examples of the “phase transfer catalyst” include tetra(n-butyl)ammoniumbromide, tetra(n-butyl)ammonium hydrogensulfate and the like.

Examples of the “inert solvent” include aliphatic hydrocarbons (e.g.,hexane, pentane, cyclohexane etc.), aromatic hydrocarbons (e.g.,benzene, toluene, xylene, chlorobenzene etc.), ethers (e.g., diethylether, diisopropy ether, tert-butylmethyl ether, diphenyl ether,tetrahydrofuran, dioxane, 1,2-dimethoxyethane etc.), halogenatedhydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane,carbon tetrachloride etc.), esters (e.g., ethyl acetate etc.), ketones(e.g., acetone, methyl ethyl ketone etc.), nitrites (e.g., acetonitrile,propionitrile etc.), sulfoxides (e.g., dimethyl sulfoxide etc.), amides(e.g., N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone, hexamethylphosphoric triamide etc.), alcohols(e.g., methanol, ethanol, isopropyl alcohol, 2-butanol, tert-butanol,2-methyl-2-butanol etc.), water, a mixture of two or more thereof andthe like. Of these, dimethyl sulfoxide, N,N-dimethylformamide,N-methylpyrrolidone and the like are preferable.

The reaction temperature is generally from about 0° C. to 150° C.,preferably from about 20° C. to 130° C. The reaction time is generallyabout 1 hour to 24 hours, preferably about 1 hour to 12 hours.

The compound (cIV) thus obtained can be isolated and purified from areaction mixture by a known method, such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, phase transfer, chromatography and the like.

In the above-mentioned reaction, the reaction product from compound (cI)and compound (cII) can be isolated from the reaction mixture accordingto a conventional method, but preferably, the reaction product issubjected to the next step without isolation.

The compound (cIV) can be converted to compound (cVII) useful as apharmaceutical agent and the like, for example, according to thefollowing Reactions c2 and c3.

Reaction c2

The compound (cIV) is subjected to hydrolysis or catalytic reduction togive compound (cV).

For “hydrolysis”, compound (cIV) and a base are reacted in an inertsolvent.

The amount of use of base is about 0.1-10 equivalents, preferably 1-5equivalents, relative to compound (cIV).

Examples of the “base” include carbonate of alkali metal or alkalineearth metal (e.g., sodium carbonate, potassium carbonate etc.),hydroxide of alkali metal or alkaline earth metal (e.g., sodiumhydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide)and the like.

Examples of the “inert solvent” include aliphatic hydrocarbons (e.g.,hexane, pentane, cyclohexane etc.), aromatic hydrocarbons (e.g.,benzene, toluene, xylene, chlorobenzene etc.), ethers (e.g., diethylether, diisopropy ether, tert-butylmethyl ether, diphenyl ether,tetrahydrofuran, dioxane, 1,2-dimethoxyethane etc.), halogenatedhydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane,carbon tetrachloride etc.), esters (e.g., ethyl acetate etc.), ketones(e.g., acetone, methyl ethyl ketone etc.), nitriles (e.g., acetonitrile,propionitrile etc.), sulfoxides (e.g., dimethyl sulfoxide etc.), amides(e.g., N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone, hexamethylphosphoric triamide etc.), alcohols(e.g., methanol, ethanol, isopropyl alcohol, 2-butanol, tert-butanol,2-methyl-2-butanol etc.), water, a mixture of two or more thereof andthe like. Preferred are methanol and dimethyl sulfoxide.

The reaction temperature is generally from about 0° C. to 150° C.,preferably from about 20° C. to 130° C. The reaction time is generallyabout 1 hour to 24 hours, preferably about 1 hour to 12 hours.

For “hydrolysis”, compound (cIV) and an acid are reacted in an inertsolvent.

The amount of use of acid is about 0.1-10 equivalents, preferably 1-5equivalents, relative to compound (cIV).

Examples of the “acid” include mineral acid such as hydrochloric acid,hydrobromic acid etc., and the like.

As the “inert solvent”, for example, water and organic acid (e.g.,acetic acid etc.) and the like can be mixed for use.

The reaction temperature is generally from about 0° C. to 150° C.,preferably from about 20° C. to 130° C. The reaction time is generallyabout 1 hour to 48 hours, preferably about 1 hour to 24 hours.

For “catalytic reduction”, compound (cIV) and a catalytic amount of ametal catalyst (e.g., Raney-nickel, platinum oxide, metal palladium,palladium-carbon etc., preferably , palladium-carbon) are reacted in aninert solvent under a hydrogen pressure of 1-100 atm at 0-100° C. forabout 1-48 hours. Preferable reaction conditions are 1-10 atm hydrogenpressure, at about 20-100° C. for about 1-24 hours.

Where necessary, an acid (e.g., hydrochloric acid, phosphoric acid,perchloric acid, sulfuric acid) and the like may be added in a catalyticamount (equivalent or in excess).

Examples of the “inert solvent” include organic acids (e.g., aceticacid, propionic acid), alcohols (e.g., methanol, ethanol,isopropylalcohol, 2-butanol, tert-butanol, 2-methyl-2-butanol etc.),ethers (e.g., diethyl ether, diisopropy ether, tert-butylmethyl ether,diphenyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane etc.),aliphatic hydrocarbons (e.g., hexane, pentane, cyclohexane etc.),aromatic hydrocarbons (e.g., benzene, toluene, xylene, chlorobenzeneetc.), water, a mixture of two or more thereof and the like.

The compound (cV) thus obtained can be isolated and purified from areaction mixture by a known method, such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, phase transfer, chromatography and the like.

Reaction c3

The compound (cV) is subjected to sulfonylation or halogenation reactionand then reacted with compound (cVI) to give compound (cVII).Specifically, compound (cV) and a sulfonylating agent or halogenatingagent are reacted in an inert solvent in the presence of a base, wheredesired.

When the compound (cVI) is on the market, a commercially availableproduct thereof may be used as it is, or compound (cVI) may be producedaccording to a method known per se, a method analogous thereto, and thelike.

The amount of use of sulfonylating agent is about 0.1-10 equivalents,preferably 1-3 equivalents, relative to compound (CV).

The amount of use of halogenating agent is about 0.1-10 equivalents,preferably 1-3 equivalents, relative to compound (cV).

The amount of use of base is about 0.1-10 equivalents, preferably 1-3equivalents, relative to compound (cV).

Examples of the “sulfonylating agent”, include R⁵—SO₂Cl such asmethanesulfonyl chloride, p-toluenesulfonyl chloride etc., and the like.

Examples of the “halogenating agent” include thionyl chloride, oxalylchloride and the like.

Examples of the “base” include carbonate of alkali metal or alkalineeach metal (e.g., sodium carbonate, potassium carbonate etc.), hydroxideof alkali metal or alkaline each metal (e.g., sodium hydroxide,potassium hydroxide, lithium hydroxide, calcium hydroxide), organic base(e.g., diisopropylethylamine, triethylamine, pyridine etc.) and thelike.

Examples of the “inert solvent” include aliphatic hydrocarbons (e.g.,hexane, pentane, cyclohexane etc.), aromatic hydrocarbons (e.g.,benzene, toluene, xylene, chlorobenzene etc.), ethers (e.g., diethylether, diisopropy ether, tert-butylmethyl ether, diphenyl ether,tetrahydrofuran, dioxane, 1,2-dimethoxyethane etc.), halogenatedhydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane,carbon tetrachloride etc.), esters (e.g., ethyl acetate etc.), ketones(e.g., acetone, methyl ethyl ketone etc.), nitrites (e.g., acetonitrile,propionitrile etc.), sulfoxides (e.g., dimethyl sulfoxide etc.), amides(e.g., N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone, hexamethylphosphoric triamide etc.), alcohols(e.g., methanol, ethanol, isopropyl alcohol, 2-butanol, tert-butanol,2-methyl-2-butanol etc.) and a mixture of two or more of these.Preferred are tetrahydrofuran, acetonitrile, acetone and the like.

The reaction temperature is generally from about −40° C. to 100° C.,preferably from about −20° C. to 80° C. The reaction time is generallyabout 1 hour to 12 hours, preferably about 1 hour to 6 hours.

Then, the thus-obtained reaction mixture and compound (cVI) are reactedin an inert solvent in the presence of a base and(or) a phase transfercatalyst, where desired, to give compound (cVII).

When the compound (cVI) is on the mark t, a commercially availableproduct thereof may be used as it is, or compound (cVI) may be producedaccording to a method known per se, a method analogous thereto, and thelike.

The amount of use of compound (cVI) is about 0.1-10 equivalents,preferably about 1-3 equivalents, relative to compound (cV).

The amount of use of base is about 1-100 equivalents, preferably about1-10 equivalents, relative to compound (cV).

The amount of use of the phase transfer catalyst is about 0.01-1equivalent, preferably about 0.01-0.3 equivalent, relative to compound(cV).

Examples of the “base” include carbonate of alkali metal or alkalineearth metal (e.g., sodium carbonate, potassium carbonate etc.),hydroxide of alkali metal or alkaline earth metal (e.g., sodiumhydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide)and the like.

Examples of the “phase transfer catalyst” include tetra(n-butyl)ammoniumbromide, tetra(n-butyl)ammonium hydrogensulfate and the like.

Examples of the “inert solvent” include aliphatic hydrocarbons (e.g.,hexane, pentane, cyclohexane etc.), aromatic hydrocarbons (e.g.,benzene, toluene, xylene, chlorobenzene etc.), ethers (e.g., diethylether, diisopropy ether, tert-butylmethyl ether, diphenyl ether,tetrahydrofuran, dioxane, 1,2-dimethoxyethane etc.), halogenatedhydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane,carbon tetrachloride etc.), esters (e.g., ethyl acetate etc.), ketones(e.g., acetone, methyl ethyl ketone etc.), nitrites (e.g., acetonitrile,propionitrile etc.), sulfoxides (e.g., dimethyl sulfoxide etc.), amides(e.g., N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone, hexamethylphosphoric triamide etc.), alcohols(e.g., methanol, ethanol, isopropyl alcohol, 2-butanol, tert-butanol,2-methyl-2-butanol etc.), water, a mixture of two or more thereof andthe like. Preferred are tetrahydrofuran, acetonitrile, acetone, waterand the like.

The reaction temperature is generally from about 0° C. to 150° C.,preferably from about 20° C. to 130° C. The reaction time is generallyabout 1 hour to 24 hours, preferably about 1 hour to 12 hours.

The compound (cVII) thus obtained can be isolated and purified from areaction mixture by a known method, such as concentration, concentrationunder reduced pressure, solvent extraction, crystallization,recrystallization, phase transfer, chromatography and the like.

The compound (cVII) useful as a pharmaceutical agent and the like can bealso produced according to the following Reactions c4-c5.

Reaction c4

A reaction mixture of compound (cI) and compound (cII) is reacted withcompound (cIII), and then the obtained compound is subjected tohydrolysis to give compound (cV).

The conditions for “a reaction mixture of compound (cI) and compound(cII) is reacted with compound (cIII)” are the same as in Reaction c1.

The “hydrolysis” only needs to follow the reaction described in Reactionc2, and the amount of use of base is about 0.1-10 equivalents,preferably 1-5 equivalents, relative to compound (cI). The amount of useof acid is about 0.1-10 equivalents, preferably 1-5 equivalents,relative to compound (cI).

Reaction c5

The compound (cV) obtained in Reaction c4 is subjected to sulfonylationor halogenation and then reacted with compound (cVI) to give compound(cVII).

The reaction conditions are the same as in Reaction c3.

The compound (cVIIa) useful as a pharmaceutical agent and the like canbe also produced according to the following Reaction c6 or Reaction c7.

Reaction c6

A reaction mixture of compound (cIa) and compound (cII) is subjected tohydrolysis and the obtained compound (cVa) is subjected to sulfonylationor halogenation and then reacted with compound (cVI) to give compound(cVIIa).

This reaction only needs to follow the above-mentioned Reactions c1-c3.As a usable “base”, for example, carbonate of alkali metal or alkalineearth metal (e.g., sodium carbonate, potassium carbonate etc.) and thelike are preferable.

Reaction c7

A reaction mixture of compound (cIa) and compound (cII) is reacted withcompound (cVI) to give compound (cVIIa).

This reaction only needs to follow the above-mentioned Reactions c1-c3.

The compounds (aVa), (aVb), (bX), (bXI) and (cVII) [inclusive ofcompound (cVIIa)] are useful as pharmaceutical agents, agriculturalchemicals and the like.

The compounds (aVa), (aVb), (bX), (bXI) and (cVII) have a tyrosinekinase inhibitory action and can be used for the prophylaxis ortreatment of tyrosine kinase-dependent diseases in mammal. The tyrosinekinase-dependent diseases include diseases caused by enhanced cellproliferation due to abnormal tyrosine kinase enzyme activity.Furthermore, since compounds (aVa), (aVb), (bX), (bXI) and (cVII)specifically inhibit HER2 tyrosine kinase, they are useful as atherapeutic agent for inhibiting growth of cancer that expresses HER2,or as an agent for preventing metastasis of hormone dependent cancer tohormone non-dependent cancer. That is, compounds (aVa), (aVb) (bX),(bXI) and (cVII) can be used as safe agents for the prophylaxis ortreatment of diseases caused by abnormal cell growth such as variouscancers (particularly breast cancer, prostate cancer, pancreatic cancer,stomach cancer), atherosclerosis, angiogenesis (e.g., angiogenesisaccompanying growth of solid tumor and sarcoma, angiogenesis associatedwith tumor metastasis, angiogenesis associated with diabetic retinopathyetc.), viral diseases (HIV infection etc.) and the like. The tyrosinekinase-dependent diseases further include abnormal tyrosine kinaseenzyme activity-related cardiovascular diseases. Therefore, thecompounds (aVa), (aVb), (bX), (bXI) and (cVII) can be also used as anagent for the prophylaxis or treatment of cardiovascular diseases suchas restenosis.

The compounds (aVa), (aVb), (bX), (bXI) and (cVII) have a tyrosinekinase inhibitory action and can be used for the prophylaxis ortreatment of tyrosine kinase-dependent diseases in mammal. The tyrosinekinase-dependent diseases include diseases caused by enhanced cellproliferation due to abnormal tyrosine kinase enzyme activity.Furthermore, since compounds (aVa), (aVb), (bX), (bXI) and (cVII)specifically inhibit HER2 tyrosine kinase, they are useful as atherapeutic agent for inhibiting growth of cancer that expresses HER2,or as an agent for preventing metastasis of hormone dependent cancer tohormone non-dependent cancer.

That is, compounds (aVa), (aVb), (bX), (bXI) and (cVII) can be used assafe agents for the prophylaxis or treatment of diseases caused byabnormal cell growth such as various cancers (particularly breastcancer, prostate cancer, pancreatic cancer, stomach cancer, lung cancer,colon cancer, rectal cancer, esophageal cancer, duodenal carcinoma,tongue cancer, pharyngeal cancer, brain tumor, neurinomatosis, non-smallcell lung cancer, small cell lung carcinoma, liver cancer, kidneycancer, bile duct cancer, cancer of uterine body, cervical carcinoma,ovarian cancer, bladder cancer, skin cancer, angiomatosis, malignantlymphoma, malignant melanoma, thyroid cancer, bone tumor, angiofibroma,retinal sarcoma, penile cancer, childhood solid cancer, Kaposi'ssarcoma, AIDS related Kaposi's sarcoma, cancer of maxillary sinus,fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, leukemia etc.),atherosclerosis, angiogenesis (e.g., angiogenesis accompanying growth ofsolid tumor and sarcoma, angiogenesis associated with tumor metastasis,angiogenesis associated with diabetic retinopathy etc.), viral diseases(HIV infection and the like.

The tyrosine kinase-dependent diseases further include abnormal tyrosinekinase enzyme activity-related cardiovascular diseases. Therefore, thecompounds (aVa), (aVb), (bX), (bXI) and (cVII) can be also used as anagent for the prophylaxis or treatment of cardiovascular diseases suchas restenosis.

The compounds (aVa), (aVb), (bX), (bXI) and (cVII) are useful asanticancer agents for the prophylaxis or treatment of cancer,particularly breast cancer, prostate cancer, pancreatic cancer, stomachcancer, lung cancer, colon cancer and large bowel cancer.

The compounds (aVa), (aVb), (bX), (bXI) and (cVII) show low toxicity andcan be used as they are as pharmaceutical agents or as a pharmaceuticalcomposition in admixture with a pharmacologically acceptable carrierknown per se for mammal such as human, horse, cattle, dog, cat, rat,mouse, rabbit, pig, monkey and the like.

A pharmaceutical composition may contain, along with the compound (aVa),(aVb), (bX), (bXI) or (cVII), other active ingredient, such as hormonepreparation, anticancer agents (e.g., chemotherapy agent, immunotherapyagent and pharmaceutical agent inhibiting the action of cell growthfactor and receptor thereof etc.) and the like.

When the compound (aVa), (aVb), (bX), (bXI) or (cVII) is administered asa pharmaceutical agent to mammal such as human, the administration routeis oral administration in the form of, for example, tablets, capsules(inclusive of soft capsule and microcapsule), powders, granules and thelike, or parenteral administration in the form of injection,suppository, pellet and the like. By the “parenterally” is meantintravenous, intramuscular, subcutaneous, intraorgan, intranasal,intradermal, instillation, intracerebral, intrarectal, intravaginal andintraperitoneal administrations, administration into tumor,administration to the vicinity of tumor and direct administration to thefocus. While the dose of the compound (aVa), (aVb), (bX), (bXI) or(cVII) varies depending on the administration route, symptoms and thelike, when, for example, it is orally administered as an anticanceragent to a patient weighing 40 to 80 kg having, for example, breastcancer or prostate cancer, it is 0.5-100 mg/kg body weight, preferably1-50 mg/kg body weight, more preferably 1-25 mg/kg body weight, which isadministered once a day or in 2 or 3 doses a day.

The compound (aVa), (aVb), (bX), (bXI) or (cVII) is admixed with apharmacologically acceptable carrier and administered orally orparenterally as a solid preparation such as tablet, capsule, granule,powder and the like or a liquid preparation such as syrup, injection andthe like.

As the pharmacologically acceptable carrier usable for the production ofthe pharmaceutical composition, there are mentioned various conventionalorganic or inorganic carriers as a material for the preparation.Examples thereof include excipients, lubricants, binders anddisintegrators for solid preparations, and solvents, solubilizing aids,suspending agents, isotonic agents, buffers and soothing agents forliquid preparations. Where necessary, conventional additives such asantiseptics, antioxidants, coloring agents, sweeteners and the like canbe used.

As preferable examples of the excipient, there are mentioned, forexample, lactose, sucrose, D-mannitol, starch, crystalline cellulose,light anhydrous silicic acid and the like.

As preferable examples of the lubricant, there are mentioned, forexample, magnesium stearate, calcium stearate, talc, colloidal silicaand the like.

As preferable examples of the binder, there are mentioned, for example,crystalline cellulose, sucrose, D-mannitol, dextrin,hydroxypropylcellulose, hydroxypropylmethylcellulose,polyvinylpyrrolidone and the like.

As preferable examples of the disintegrator, there are mentioned, forexample, starch, carboxymethylcellulose, carboxymethylcellulose calcium,crosscarmellose, sodium carboxymethyl starch and the like.

As preferable examples of the solvent, there are mentioned, for example,injectable water, alcohol, propylene glycol, Macrogol, sesame oil, cornoil and the like.

As preferable examples of the solubilizing aid, there are mentioned, forexample, polyethylene glycol, propylene glycol, D-mannitol, benzylbenzoate, ethanol, tris-aminomethane, cholesterol, triethanolamine,sodium carbonate, sodium citrate and the like.

As preferable examples of the suspending agent, there are mentioned, forexample, surfactants such as stearyl triethanolamine, sodium laurylsulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride,benzethonium chloride, glyceryl monostearate and the like; hydrophilicpolymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodiumcarboxymethylcellulose, methylcellulose, hydroxymethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose and the like.

As preferable examples of the isotonicity agent, there are mentioned,for example, sodium chloride, glycerine, D-mannitol and the like.

As preferable examples of the buffer, there are mentioned, for example,buffers such as phosphate, acetate, carbonate, citrate and the like.

As preferable examples of the soothing agent, there are mentioned, forexample, benzyl alcohol and the like.

As preferable examples of the antiseptic, there are mentioned, forexample, p-oxybenzoates, chlorobutanol, benzyl alcohol, phenethylalcohol, dehydroacetic acid, sorbic acid and the like.

As preferable examples of the antioxidant, there are mentioned, forexample, sulfite, ascorbic acid and the like.

While the pharmaceutical composition varies depending on the dosageform, administration method, carrier and the like, it can be producedaccording to a conventional method by adding compound (aVa), (aVb),(bX), (bXI) or (cVII) generally in an amount of 0.1-95%(w/w) of theentire amount of the preparation.

In addition, by (1) administering an effective amount of compound (aVa),(aVb), (bX), (bXI) or (cVII), (2) (i) administering an effective amountof a different anticancer agent, (ii) administering an effective amountof a hormone preparation, or (iii) by combining 1 to 3 kinds from agroup consisting of therapies without medicine, cancer can be moreeffectively prevented or treated. As the therapy without medicine, thereare mentioned, for example, operation, radiation therapy, gene therapy,thermotherapy, cryotherapy, laser cauterization therapy and the like,and two or more of these can be combined.

For example, the compound of the present invention can be used incombination with other hormone preparations, anticancer agents (e.g.,chemotherapy agent, immunotherapy agent and pharmaceutical agentinhibiting the action of cell growth factor and receptor thereof) andthe like (hereinafter to be briefly referred to as combination drug).

While the compounds (aVa), (aVb), (bX), (bXI) or (cVII) shows a superioranticancer effect even when used as a single agent, when it is used incombination with one or more of the above-mentioned combination drugs(combined use of plural agents), the effect can be reinforcedfurthermore.

Examples of the “hormone preparation” include fosfestrol,diethylstilbestrol, chlorotrianiseline, medroxyprogesterone acetate,megesterol acetate, chlormadinone acetate, cyproterone acetate, danazol,allylestrenol, gestrinone, mepartricine, raloxifene, ormeloxifene,levormeloxifene, antiestrogen (e.g., tamoxifen citrate, toremifenecitrate etc.), contraceptive pill, mepitiostane, testolactone,aminoglutethimide, LH—RH agonist (e.g., goserelin acetate, buserelin,leuprorelin etc.), droloxifene, epitiostanol, ethinylestradiolsulfonate, aromatase inhibitor (e.g., fadrozole hydrochloride,anastrozole, letrozole, exemestane, vorozole, formestane etc.),antiandrogen (e.g., flutamide, bicalutamide, nilutamide etc.),5α-reductase inhibitor (e.g., finasteride, epristeride etc.),adrenocortical hormone preparation (e.g., dexamethasone, prednisolone,betamethasone, triamcinolone etc.), androgen synthesis inhibitor (e.g.,abiraterone etc. and lyase inhibitor), retinoid and an agent to delaymetabolism of retinoid (e.g., liarozole etc.) and the like. Of these,LH—RH agonist (e.g., goserelin acetate, buserelin, leuprorelin etc.) ispreferable.

Examples of the “chemotherapy agent” include alkylating agent,antimetabolite, carcinostatic antibiotics, plant alkaloid and the like.

Examples of the “alkylating agent” include nitrogen mustard, nitrogenmustard-n-oxide hydrochloride, chrorambucil, cyclophosphamide,ifosfamide, thiotepa, carboquone, improsulfan tosilate, busulfan,nimustine hydrochloride, mitobronitol, melphalan, dacarbazine,ranimustine, sodium estramustine phosphate, triethylene melamine,carmustine, lomustine, streptozocin, pipobroman, etoglucide, altretamin,ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine,pumitepa, ribomustin, temozolomide, treosulfan, trophosphamide,zinostatin stimalamer, carboquone, adozelesin, cystemstin, bizelesin,platinym complex (carboplatin, cisplatin, miboplatin, nedaplatin,oxaliplatin etc.) and the like.

Examples of the “antimetabolite” include mercaptopurine,6-mercaptopurine riboside, thioinosine, methotrexate, enocitabine,cytarabine, cytarabine ocphosphate, ancitabine hydrochloride, 5-FUpharmaceutical agents (e.g., fluorouracil, tegafur, UFT, doxifluridine,carmofur, galocitabine, emitefur etc.), aminopterin, calcium leucovorin,tabloid, butocin, calcium folinate, calcium levofolinate, cladribine,emitefur, fludarabine, gemcitabine, hydroxycarbamide, pentostatin,piritrexim, idoxuridine, mitoguazone, tiazofurin, ambamstine and thelike.

Examples of the “carcinostatic antibiotics” include anthracyclincarcinostatic agents (doxorubicin hydrochloride, daunorubicinhydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride,epirubicin hydrochloride etc.), actinomycin D, actinomycin C., mitomycinC., chromomycin A3, bleomycin hydrochloride, bleomycin sulfate,peplomycin sulfate, neocarzinostatin, mithramycin, sarcomycin,carzinophilin, mitotane, zorubicin hydrochloride, mitoxantronehydrochloride, idarubicin hydrochloride and the like.

Examples of the “plant alkaloid” include vinca alkaloid carcinostaticagents (vinblastine sulfate, vincristine sulfate, vindesine sulfateetc.), taxan anticancer agents (paclitaxel, docetaxel etc.), etoposide,etoposide phosphate, teniposide, vinorelbine and the like.

Examples of the “immunotherapeutic agent” (BRM) include picibanil,krestin, sizofiran, lentinan, ubenimex, interferon, interleukin,macrophage colony stimulating factor, granulocyte-colony stimulatingfactor, erythropoietin, lymphotoxin, BCG vaccine, Corynebacteriumparvum, levamisole, polysaccharide K, procodazol and the like.

As the “cell growth factor” in the “pharmaceutical agent inhibitingaction of the cell growth factor and its receptor”, any substance can beused as long as it enhances proliferation of cells. In general, a factorwhich is a peptide having a molecular weight of not more than 20,000,and which can show effect upon binding with receptor at a lowconcentration is exemplified. Specific examples include (1) EGF(epidermal growth factor) or a substance having substantially the sameactivity therewith [e.g., EGF, heregulin (HER2 ligand) etc.], (2)insulin or a substance having substantially the same activity therewith[e.g., insulin, IGF (insulin-like growth factor)-1, IGF-2 etc.], (3) FGF(fibroblast growth factor) or a substance having substantially the sameactivity therewith [e.g., acidic FGF, basic FGF, KGF (keratinocytegrowth factor), FGF-10 etc.], (4) other cell growth factors [e.g., CSF(colony stimulating factor), EPO (erythropoietin), IL-2(interleukin-2),NGF (nerve growth factor), PDGF (platelet-derived growth factor), TGFβ(transforming growth factor β), HGF (hepatocyte growth factor), VEGF(vascular endothelial growth factor) etc.] and the like.

The “receptor of the cell growth factor” may be any receptor as long asit has a binding ability with the above-mentioned cell growth factor.Specific examples include EGF receptor, heregulin receptor (HER2),insulin receptor, IGF receptor, FGF receptor-1, FGF receptor-2, HGFreceptor (c-met), VEGF receptor, SCF receptor (c-kit), and the like.

Examples of the “pharmaceutical agent inhibiting action of the cellgrowth factor” include herceptin (HER2 antibody), GLEEVEC (c-met, c-kit,abl inhibitor), Iressa (EGF receptor inhibitor) and the like.

In addition to the aforementioned pharmaceutical agents, L-asparaginase,aceglatone, procarbazine hydrochloride, cobalt protoporphyrin complex,mercurial hematoporphyrin sodium, topoisomerase I inhibitor (e.g.,irinotecan, topotecan etc.), topoisomerase II inhibitor (e.g.,sobuzoxane etc.), differentiation inducing agent (e.g., retinoid,vitamine D etc.), angiogenesis inhibitor, α-blocker (e.g., tamsulosinhydrochloride etc.) and the like can be also used.

Of the above-mentioned combination drugs, LH—RH agonist (e.g., goserelinacetate, buserelin acetate, leuprorelin acetate etc.), herceptin (HER2antibody) and the like are preferable.

For the combined use of compound (aVa), (aVb), (bX), (bXI) or (cVII) andcombination drug, the time of administration of compound (aVa), (aVb),(bX), (bXI) or (cVII) and combination drug is not limited. The compound(aVa), (aVb), (bX), (bXI) or (cVII) and combination drug may besimultaneously administered to an administration object or administeredin a staggered manner. The dose of the combination drug only needs tofollow the dose clinically employed, and can be determined asappropriate depending on the administration object, administrationroute, disease, combination and the like.

The mode of administration of the compound (aVa), (aVb), (bX), (bXI) or(cVII) and combination drug(s) is not particularly limited, and may beany as long as the compound (aVa), (aVb), (bX), (bXI) or (cVII) andcombination drug(s) are combined on administration. Such administrationmode is exemplified by (1) administration of a single preparationobtained by simultaneously formulating the compound (aVa), (aVb), (bX),(bXI) or (cVII) and combination drug(s) into a preparation, (2)simultaneous administration by the same administration route of twokinds of preparations obtained by separately formulating the compound(aVa), (aVb), (bX), (bXI) or (cVII) and combination drug(s) intopreparations, (3) staggered administration by the same administrationroute of two kinds of preparations obtained by separately formulatingthe compound (aVa), (aVb), (bX), (bXI) or (cVII) and combination drug(s)into preparations, (4) simultaneous administration by differentadministration routes of two kinds of preparations obtained byseparately formulating the compound (aVa), (aVb), (bX), (bXI) or (cVII)and combination drug(s) into preparations, (5) staggered administrationby different administration routes of two kinds of preparations obtainedby separately formulating the compound (aVa), (aVb), (bX), (bXI) or(cVII) and combination drug(s) into preparations (e.g., administrationin the order of compound (aVa), (aVb), (bX), (bXI) or (cVII)→combinationdrug, and administration in the reversed order) and the like. Thesemodes of administrations are collectively referred to in the followingas a combination agent of the present invention.

The combination agent of the present invention has low toxicity and canbe administered safely by admixing the compound (aVa), (aVb), (bX),(bXI) or (cVII) and/or combination drug(s) with, for example, apharmacologically acceptable carrier according to a method known per seto give a pharmaceutical composition, such as tablets (inclusive ofsugar-coated tablets and film-coated tablets), powders, granules,capsules, (inclusive of soft capsules), liquids, injections,suppositories, sustained release agents and the like, for oral orparenteral (e.g., topical, rectal or intravenous administration)administration. An injection can be administered intravenously,intramuscularly, subcutaneously, into the organ, intranasally,intradermally, by instillation, intracerebrally, intrarectally,intravaginally, intraperitoneally, into tumor, to the vicinity of tumoror directly to the focus.

As the pharmacologically acceptable carrier usable for the production ofthe combination agent of the present invention, there are mentionedthose usable for the aforementioned pharmaceutical composition.

The content ratio of the compound (aVa), (aVb), (bX), (bXI) or (cVII)and combination drug in the combination agent of the present inventioncan be appropriately determined depending on the administration object,administration route, disease and the like.

For example, the content of the compound (aVa), (aVb), (bX), (bXI) or(cVII) in the combination agent of the present invention is generallyabout 0.01-100 wt %, preferably about 0.1-50 wt %, more preferably about0.5-20 wt %, based on the preparation in total, though they may changedepending on the preparation form.

The content of the combination drug in the combination agent of thepresent invention is generally about 0.01-100 wt %, preferably about0.1-50 wt %, more preferably about 0.5-20 wt %, based on the preparationin total, though may change depending on the preparation form.

The content of the additive in the combination agent of the presentinvention varies depending on the form of the preparation. It isgenerally about 1-99.99 wt %, preferably about 10-90 wt %, based on thepreparation in total.

The same contents are employed when the compound (aVa), (aVb), (bX),(bXI) or (cVII) and combination drug(s) are formulated separately intopreparations.

These preparations can be produced by a method known per se, which isgenerally employed for the preparation steps.

For example, the compound (aVa), (aVb), (bX), (bXI) or (cVII), or acombination drug can be prepared into an aqueous injection together witha dispersant (e.g., Tween 80 (ATLASPOWDER USA), HCO60 (NIKKO CHEMICALS),polyethylene glycol, carboxymethylcellulose, sodium arginate,hydroxypropylmethylcellulose, dextrin etc.), a stabilizer (e.g.,ascorbic acid, sodium pyrosulfite etc.), a surfactant (e.g., polysorbate80, Macrogol etc.), a solubilizer (e.g., glycerine, ethanol etc.), abuffering agent (e.g., phosphoric acid, alkali metal salt thereof,citric acid, alkali metal salt thereof etc.), an isotonicity agent(e.g., sodium chloride, potassium chloride, mannitol, sorbitol, glucoseetc.), a pH adjusting agent (hydrochloric acid, sodium hydroxide etc.),a preservative (ethyl p-hydroxybenzoate, benzoic acid, methylparaben,propylparaben, benzyl alcohol etc.), a solubilizer (e.g., conc.glycerine, meglumine etc.), a solubilizing aid (e.g., propylene glycol,sucrose etc.), a soothing agent (e.g., glucose, benzyl alcohol etc.) andthe like, or into an oil-based injection by dissolving, suspending oremulsifying in a vegetable oil (e.g., olive oil, sesame oil, cottonseedoil, corn oil etc.) or a solubilizing aid such as propylene glycol etc.,and used as an injection.

An oral formulation can be produced by a method known per se by admixingthe compound (aVa), (aVb), (bX), (bXI) or (cVII), or a combination drugwith an excipient (e.g., lactose, sucrose, starch and the like), adisintegrant (e.g., starch, calcium carbonate and the like), a binder(e.g., starch, gum arabic, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose and the like) or a lubricant (e.g.,talc, magnesium stearate, polyethylene glycol 6000 and the like) andcompressing the mixture, optionally followed by a coating process knownper se for the purpose of masking a taste, forming an enteric coat, orachieving a sustained release. Such coating may, for example, behydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose,hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, Pluronic F68,cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate,hydroxymethyl cellulose acetate succinate, Eudragid (ROHME, Germany, acopolymer of methacrylic acid and acrylic acid), a dye (e.g., colcothar,titanium oxide etc.) and the like. The preparation for oraladministration may be either a rapid release preparation or a sustainedrelease preparation.

A suppository can be produced by making the compound (aVa), (aVb), (bX),(bXI) or (cVII), or a combination drug into an oily or aqueous solid,semisolid or liquid composition. Examples of the oily base to be usedfor such a composition include glyceride of higher fatty acid (e.g.,cacao butter, Witepsol (Dynamit Nobel, Germany etc.), medium fatty acid(e.g., migliol (Dynamit Nobel, Grmany etc.), vegetable oil (e.g., sesameoil, soybean oil, cottonseed oil etc.) and the like. Examples of theaqueous gel base include natural gums, cellulose derivative, vinylpolymer, acrylate polymer and the like

Examples of the above-mentioned sustained release preparation includesustained release microcapsule and the like.

A sustained release microcapsule can be prepared by a method known perse. For example, a sustained release preparation shown in the following[2] is preferably formed and administered.

The compound (aVa), (aVb), (bX), (bXI) or (cVII) is preferably formedinto a preparation for oral administration such as a solid preparation(e.g., powder, granule, tablet, capsule) and the like, or a preparationfor rectal administration such as a suppository and the like.Particularly, a preparation for oral administration is preferable.

The combination drug can be prepared into the above-mentioned dosageform according to the kind of the drug.

In the following, [1] an injection of the compound (aVa), (aVb), (bX),(bXI) or (cVII), or a combination drug and preparation thereof, [2] asustained release preparation or a rapid release preparation of thecompound (aVa), (aVb), (bX), (bXI) or (cVII), or a combination drug andpreparation thereof, and [3] a sublingual tablet, buccal or oral cavityrapid disintegrator of the compound (aVa), (aVb), (bX), (bXI) or (cVII),or a combination drug and preparation thereof are concretely explained.

[1] Injection and Preparation Thereof

An injection containing the compound (aVa), (aVb), (bX), (bXI) or(cVII), or a combination drug dissolved in water is preferable. Theinjection may contain benzoate and/or salicylate.

The injection is obtained by dissolving both the compound (aVa), (aVb),(bX), (bXI) or (cVII), or a combination drug and, where desired,benzoate and/or salicylate in water.

The salt of the above-mentioned benzoic acid and salicylic acidincludes, for example, alkali metal salts such as sodium, potassium andthe like, alkaline earth metal salts such as calcium, magnesium and thelike, ammonium salt, meglumine salt, and organic acid salt such astrometamol and the like, and the like.

The concentration of the compound (aVa), (aVb), (bX), (bXI) or (cVII),or a combination drug in the injection is about 0.5-50 w/v %, preferablyabout 3-20 w/v %. The concentration of the benzoate and/or salicylate ispreferably 0.5-50 w/v %, more preferably 3-20 w/v %.

This agent may contain additives generally used for injections, such asa stabilizer (e.g., ascorbic acid, sodium pyrosulfite etc.), asurfactant (e.g., polysorbate 80, Macrogol etc.), a solubilizer (e.g.,glycerine, ethanol etc.), a buffering agent (e.g., phosphoric acid,alkali metal salt thereof, citric acid, alkali metal salt thereof etc.),an isotonicity agent (e.g., sodium chloride, potassium chloride etc.), adispersing agent (e.g., hydroxypropylmethylcellulose, dextrin), a pHadjusting agent (hydrochloric acid, sodium hydroxide etc.), apreservative (ethyl p-hydroxybenzoate, benzoic acid etc.), a solubilizer(e.g., conc. glycerine, meglumine etc.), a solubilizing aid (e.g.,propylene glycol, sucrose etc.), a soothing agent (e.g., glucose, benzylalcohol etc.) and the like as appropriate. These additives are added ina proportion generally employed for injections.

The injection is preferably adjusted to pH 2-12, preferably 2.5-8.0, bythe use of a pH adjusting agent.

The injection can be obtained by dissolving both the compound (aVa),(aVb), (bX), (bXI) or (cVII), or a combination drug and, where desired,benzoate and/or salicylate, and where necessary, the above-mentionedadditives in water. These may be dissolved in any order in a suitablemanner as in conventional production of injections.

The injectable aqueous solution is preferably heated and, in the samemanner as with conventional injections, subjected to, for example,sterilization by filtration, high pressure sterilization by heating andthe like to provide an injection.

The injectable aqueous solution is preferably subjected to high pressuresterilization by heating at, for example, 100° C.-121° C. for 5 min-30min.

It may be prepared into an antibacterial solution, so that it can beused as a preparation for plural subdivided administrations.

[2] Sustained Release Preparation or Rapid Release Preparation andPreparation Thereof

A sustained release preparation wherein a core containing the compound(aVa), (aVb), (bX), (bXI) or (cVII), or a combination drug is covered ondemand with a film forming agent, such as a water-insoluble material, aswellable polymer and the like, is preferable. For example, a sustainedrelease preparation for oral administration once a day is preferable.

The water-insoluble material to be used for the film forming agent is,for example, cellulose ethers such as ethylcellulose, butylcellulose andthe like; cellulose esters such as cellulose acetate, cellulosepropionate and the like; polyvinyl esters such as poly(vinyl acetate),poly(vinyl butyrate) and the like; acrylic polymers such as acrylicacid/methacrylic acid copolymer, methyl methacrylate copolymer,ethoxyethyl methacrylate/cinnamoethyl methacrylate/aminoalkylmethacrylate copolymer, polyacrylic acid, polymethacrylic acid,methacrylic acid alkylamide copolymer, poly(methyl methacrylate),polymethacrylate, polymethacryl amide, aminoalkyl methacrylatecopolymer, poly(methacrylic anhydride) and glycidyl methacrylatecopolymer, particularly Eudragits (Rohm Pharma) such as Eudragit RS-100,RL-100, RS-30D, RL-30D, RL-PO, RS-PO (ethyl acrylate-methylmethacrylate-trimethyl chloride methacrylate-ammonium ethyl copolymer),Eudragit NE-30D (methyl methacrylate-ethyl acrylate copolymer) and thelike, and the like; hydrogenated oils such as hydrogenated castor oil(e.g., Lubri wax (Freund Inc.) and the like) and the like; waxes such ascarnauba wax, fatty acid glycerine ester, paraffin and the like;polyglycerine fatty acid ester and the like.

As the swellable polymer, a polymer having an acidic dissociable group,which shows pH-dependent swelling, is preferable, and a polymer havingan acidic dissociable group, which shows less swelling in an acidicrange, such as in the stomach, but otherwise in a neutral range, such asin the small intestine and large intestine, is preferable.

Examples of the polymer having an acidic dissociable group, which showspH-dependent swelling, include crosslinking type polyacrylic acidpolymers such as Carbomer 934P, 940, 941, 974P, 980, 1342 and the like,polycarbophil, calcium polycarbophil (all mentioned above are theproduct of BF Goodrich), HI-BIS-WAKO 103,104, 105, 304 (all beingproducts of Waco Pure Chemicals Industries, Ltd.) and the like.

The film forming agent to be used for the sustained release preparationmay further contain a hydrophilic material.

Examples of the hydrophilic material include polysaccharides optionallyhaving a sulfuric acid group such as pullulan, dextrin, alkali metalsalt of alginic acid and the like; polysaccharides having a hydroxyalkyl group or a carboxy alkyl group such as hydroxypropylcellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose and thelike; methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol,polyethylene glycol and the like.

The content of the water-insoluble material of the film forming agentfor a sustained release preparation is about 30-about 90% (w/w),preferably about 35-about 80% (w/w), more preferably about 40-75% (w/w),and the content of the swellable polymer is about 3-about 30% (w/w),preferably about 3-about 15% (w/w). The film forming agent may furthercontain a hydrophilic material, in which case the content of thehydrophilic material for film forming agent is not more than about 50%(w/w), preferably about 5-about 40% (w/w), more preferably about 5-about35% (w/w). As used herein, the above-mentioned % (w/w) is a percentagerelative to the film forming agent composition wherein the solvent(e.g., water, lower alcohol such as methanol, ethanol and the like) hasbeen removed from the film forming liquid agent.

A sustained release preparation is produced by preparing a corecontaining a drug as exemplarily mentioned below, and coating theresulting core with a film forming liquid agent prepared by dissolvingby heating or dissolving or dispersing in a solvent a water-insolublematerial, a swellable polymer and the like.

I. Preparation of Core Containing a Drug

The form of the core containing a drug (hereinafter sometimes simplyreferred to as a core) to be coated with a film forming agent is notparticularly limited, but it is preferably formed into particles such asgranules, fine granules and the like.

When the core is made of granules or fine granules, the average particlesize thereof is preferably about 150-2,000 μm, more preferably about500-about 1,400 μm.

The core can be prepared by a typical production method. For example, adrug is mixed with suitable excipients, binders, disintegrators,lubricants, stabilizers and the like, and subjected to wet extrusiongranulation, fluidized bed granulation and the like.

The drug content of the core is about 0.5-about 95% (w/w), preferablyabout 5.0-about 80% (w/w), more preferably about 30-about 70% (w/w).

Examples of the excipient to be contained in the core includesaccharides such as sucrose, lactose, mannitol, glucose and the like,starch, crystalline cellulose, calcium phosphate, cornstarch and thelike. Of these, crystalline cellulose and corn starch are preferable.

Examples of the binder include polyvinyl alcohol,hydroxypropylcellulose, polyethylene glycol, polyvinylpyrrolidone,Pluronic F68, gum arabic, gelatin, starch and the like. Examples of thedisintegrator include carboxymethylcellulose calcium (ECG505),crosscarmellose sodium (Ac-Di-Sol), crosslinked polyvinylpyrrolidone(Crospovidone), low substituted hydroxypropylcellulose (L-HPC) and thelike. Of these, hydroxypropylcellulose, polyvinylpyrrolidone and lowsubstituted hydroxypropylcellulose are preferable. Examples of thelubricant and coagulation preventive include talc, magnesium stearateand inorganic salts thereof, and examples of the lubricant includepolyethylene glycol and the like. Examples of the stabilizer includeacids such as tartaric acid, citric acid, succinic acid, fumaric acid,maleic acid and the like.

The core can be also prepared by, besides the above-mentioned productionmethods, for example, rolling granulation wherein a drug or a mixture ofa drug and an excipient, a lubricant and the like is added by smallportions while spraying a binder dissolved in a suitable solvent such aswater, lower alcohol (e.g., methanol, ethanol and the like) and the likeon an inert carrier particles to be the center of the core, a pancoating method, a fluidized bed coating method or a melt granulatingmethod. Examples of the inert carrier particle include those preparedfrom sucrose, lactose, starch, crystalline cellulose and waxes, whichpreferably have an average particle size of about 100 μm-about 1,500 μm.

To separate the drug contained in the core from the film forming agent,the surface of the core may be coated with a protective agent. Examplesof the protective agent include the aforementioned hydrophilic material,water-insoluble material and the like. As the protective agent,preferably polyethylene glycol, polysaccharides having a hydroxy alkylgroup or a carboxy alkyl group, more preferablyhydroxypropylmethylcellulose and hydroxypropylcellulose are used. Theprotective agent may contain, as a stabilizer, an acid such as tartaricacid, citric acid, succinic acid, fumaric acid, maleic acid and thelike, and a lubricant such as talc and the like. When the protectiveagent is used, the amount to be coated is about 1-about 15% (w/w),preferably about 1-about 10% (w/w), more preferably about 2-about 8%(w/w), relative to the core.

The protective agent can be coated by a typical coating method.Specifically, the protective agent is, for example, spray-coated to thecore by a fluidized bed coating method, a pan coating method, and thelike.

II. Coating of Core with a Film Forming Agent

The core obtained in the aforementioned I is coated with a film formingliquid agent prepared by dissolving by heating or dissolving ordispersing in a solvent the aforementioned water-insoluble material, apH-dependent swellable polymer, and a hydrophilic material to provide asustained release preparation.

For coating a core with a film forming liquid agent, for example, aspray coating method and the like can be employed.

The composition ratio of the water-insoluble material, swellable polymeror hydrophilic material in the film forming liquid agent is suitablydetermined such that each component of the coating film meets theaforementioned content.

The coating amount of the film forming agent is about 1-about 90% (w/w),preferably about 5-about 50% (w/w), more preferably about 5-35% (w/w),relative to the core (exclusive of the coating amount of protectiveagent).

As the solvent for the film forming liquid agent, water or organicsolvents can be used alone or in a mixture of the both. The mixing ratio(water/organic solvent: weight ratio) of water and the organic solventin the mixture can vary within the range of 1-100%, which is preferably1-about 30%. The organic solvent is not subject to any particularlimitation as long as it dissolves the water-insoluble material. Forexample, lower alcohols such as methyl alcohol, ethyl alcohol, isopropylalcohol, n-butyl alcohol and the like, lower alkanone such as acetoneand the like, acetonitrile, chloroform, methylene chloride and the likeare used. Of these, lower alcohol is preferable, and ethyl alcohol andisopropyl alcohol are particularly preferable. Water and a mixture ofwater and an organic solvent are preferably used as a solvent of thefilm forming agent. Where necessary, the film forming liquid agent maycontain an acid such as tartaric acid, citric acid, succinic acid,fumaric acid, maleic acid and the like for the stabilization of the filmforming liquid agent.

When spray coating is employed, the method follows a conventionalcoating method, which specifically includes spray coating the core witha film forming liquid agent by, for example, a fluidized bed coatingmethod, a pan coating method and the like. Where necessary, talc,titanium oxide, magnesium stearate, calcium stearate, light anhydroussilicic acid and the like may be added as a lubricants and glycerinefatty acid ester, hydrogenated castor oil, triethyl citrate, cetylalcohol, stearyl alcohol and the like may be added as a plasticizer.

After coating with a film forming agent, an antistatic agent such astalc and the like may be added as necessary.

A rapid release preparation may be a liquid (solution, suspension,emulsion and the like) or a solid (particle, pill, tablet and the like).An agent for oral administration, and an agent for parenteraladministration, such as injection and the like, are used, withpreference given to an agent for oral administration.

A rapid release preparation may generally contain, in addition to thedrug, which is an active ingredient, carriers, additives and excipients(hereinafter sometimes simply referred to as excipient) conventionallyused in the field of preparation. The excipient for a preparation is notsubject to any particular limitation as long as it is conventionallyemployed as an excipient for a preparation. For example, the excipientfor the oral solid preparation includes lactose, starch, corn starch,crystalline cellulose (Asahi Kasei Corporation, Avicel PH101 and thelike), powder sugar, granulated sugar, mannitol, light anhydrous silicicacid, magnesium carbonate, calcium carbonate, L-cysteine and the like,preferably corn starch and mannitol and the like. These excipients maybe used alone or in combination. The content of the excipient is, forexample, about 4.5-about 99.4 w/w%, preferably about 20-about 98.5 w/w%,more preferably about 30-about 97 w/w%, of the total amount of the rapidrelease preparation.

The drug content of the rapid release preparation is appropriatelydetermined from the range of about 0.5-about 95%, preferably about1-about 60%, of the total amount of the rapid release preparation.

When the rapid release preparation is an oral solid preparation, itgenerally contains a disintegrator in addition to the above-mentionedcomponents. Examples of the disintegrator include calciumcarboxymethylcellulose (Gotoku Pharmaceutical Co., Ltd., ECG-505),crosscarmellose sodium (e.g., Asahi Kasei Corporation, acjizol),Crospovidone (e.g., colidone CL, BASF), low substitutedhydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd.), carboxymethylstarch (Matsutani Chemical Industry Co., Ltd., sodium carboxymethylstarch (Kimura Sangyo, exprotab), partially α starch (PCS, Asahi KaseiCorporation) and the like. For example, one capable of disintegratinggranules by water absorption, swelling, forming a channel between theactive ingredient constituting the core and an excipient upon contactwith water and the like can be used. These disintegrators can be usedalone or in combination. The amount of the disintegrator isappropriately determined depending on the kind of the combination drugto be used and amount thereof, design of the release preparation and thelike. It is generally about 0.05-about 30 w/w %, preferably about0.5-about 15 w/w %, relative to the total amount of the rapid releasepreparation.

When the rapid release preparation is an oral preparation, the oralsolid preparation may further contain, in addition to theabove-mentioned composition, typical additives used for solidpreparation on demand. Examples of the additive include a binder (e.g.,sucrose, gelatin, gum arabic powder, methylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose,carboxymethylcellulose, polyvinylpyrrolidone, Pullulan, dextrin etc.), alubricant (e.g., polyethylene glycol, magnesium stearate, talc, lightanhydrous silicic acid (e.g., Aerosil (Nippon Aerosil)), a surfactant(e.g., anionic surfactant such as sodium alkylsulfate etc., non-ionicsurfactant such as polyoxyethylene fatty acid ester andpolyoxyethylenesorbitan fatty acid ester, polyoxyethylene castor oilderivative etc., and the like), a coloring agent (e.g., tar color,caramel, iron oxide red, titanium oxide, riboflavins), where necessary,a corrigent (e.g., a sweetener, flavor etc.), an absorbent, anantiseptic, a moistening agent, an antistatic agent and the like. As thestabilizer, an organic acid such as tartaric acid, citric acid, succinicacid, fumaric acid and the like may be added.

Examples of the above-mentioned binder preferably includehydroxypropylcellulose, polyethylene glycol, polyvinylpyrrolidone andthe like.

The rapid release preparation can be prepared based on the conventionalpreparation method, by mixing each of the aforementioned components, andwhere necessary, further kneading and forming. The above-mentionedmixing can be performed by a conventional method, such as mixing,kneading and the like. Specifically, for example, when a rapid releasepreparation is formed into particles, a vertical granulator, a universalkneader (HATA Tekkohjo), a fluidized bed granulator FD-5S (PowrexCorporation) and the like are used for mixing, which is followed bygranulating by wet extrusion granulation, fluidized bed granulation andthe like, to give the preparation, as in the preparation of the core ofthe aforementioned sustained release preparation.

The rapid release preparation and the sustained release preparation thusobtained may be used as they are. Alternatively, after suitable separatepreparation along with an excipient for a preparation and the likeaccording to a conventional method, they may be administeredsimultaneously or at optional administration intervals. Alternatively,they may be each prepared into a single preparation for oraladministration (e.g., granule, fine granule, tablet, capsule and thelike) as they are or together with excipient for preparation and thelike as appropriate. The both preparations are converted to granules orfine granules and filled in a single capsule and the like to give apreparation for oral administration.

[3] A Sublingual Tablet, Buccal or Oral Cavity Rapid Disintegrator andPreparation Thereof

The sublingual tablet, buccal preparation and oral cavity rapiddisintegrator may be a solid preparation such as tablet and the like oran oral cavity mucous membrane adhesion tablet (film).

As the sublingual tablet, buccal or oral cavity rapid disintegrator, apreparation containing the compound (aVa), (aVb), (bX), (bXI) or (cVII),or a combination drug and an excipient is preferable. It may containauxiliaries such as a lubricant, an isotonic agent, a hydrophiliccarrier, a water dispersible polymer, a stabilizer and the like. Foreasy absorption and enhanced bioavailability, β-cyclodextrin orβ-cyclodextrin derivative (e.g., hydroxypropyl-β-cyclodextrin and thelike) and the like may be contained.

Examples of the above-mentioned excipient include lactose, sucrose,D-mannitol, starch, crystalline cellulose, light anhydrous silicic acidand the like. Examples of the lubricant include magnesium stearate,calcium stearate, talc, colloidal silica and the like, particularlymagnesium stearate and colloidal silica are preferable. Examples of theisotonicity agent include sodium chloride, glucose, fructose, mannitol,sorbitol, lactose, saccharose, glycerine, urea and the like,particularly mannitol is preferable. Examples of the hydrophilic carrierinclude swellable hydrophilic carriers such as crystalline cellulose,ethylcellulose, crosslinked polyvinylpyrrolidone, light anhydroussilicic acid, silicic acid, dicalcium phosphate, calcium carbonate andthe like, particularly crystalline cellulose (e.g., microcrystallinecellulose and the like) is preferable. Examples of the water dispersiblepolymer include gum (e.g., gum tragacanth, acacia gum, guar gum),alginate (e.g., sodium alginate), cellulose derivative (e.g.,methylcellulose, carboxymethylcellulose, hydroxymethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose), gelatin, solublestarch, polyacrylic acid (e.g., carbomer), polymethacrylic acid,polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone,polycarbofil, ascorbic palmitate and the like, with preference given tohydroxypropylmethylcellulose, polyacrylic acid, alginate, gelatin,carboxymethylcellulose, polyvinylpyrrolidone, polyethylene glycol andthe like. Particularly, hydroxypropylmethylcellulose is preferable.Examples of the stabilizer include cysteine, thiosorbitol, tartaricacid, citric acid, sodium carbonate, ascorbic acid, glycine, sodiumsulfite and the like, particularly, citric acid and ascorbic acid arepreferable.

The sublingual tablet, buccal and oral cavity rapid disintegrator can beproduced by mixing the compound (aVa), (aVb), (bX), (bXI) or (cVII), ora combination drug and an excipient by a method know per se. Wheredesired, the above-mentioned auxiliaries such as a lubricant, anisotonic agent, a hydrophilic carrier, a water dispersible polymer, astabilizer, a coloring agent, a sweetener, an antiseptic and the likemay be contained. After mixing the above-mentioned componentssimultaneously or with time staggering, the mixture is compressionformed under pressure to give sublingual tablet, buccal or oral cavityrapid disintegrator. To achieve a suitable hardness, a solvent such aswater, alcohol and the like is used to moisten or wet as necessarybefore and after the compression forming. After the forming, the tabletsmay be dried.

When a mucous membrane adhesion tablet (film) is produced, the compound(aVa), (aVb), (bX), (bXI) or (cVII), or a combination drug and theabove-mentioned water dispersible polymer (preferably,hydroxypropylcellulose, hydroxypropylmethylcellulose), an excipient andthe like are dissolved in a solvent such as water and the like, and theobtained solution is cast to give a film. In addition, an additive suchas a plasticizer, a stabilizer, an antioxidant, a preservative, acoloring agent, a buffer, a sweetener and the like may be added. Toimpart suitable elasticity to the film, glycols such as polyethyleneglycol, propylene glycol and the like may be added, and to increaseadhesion of the film to the oral cavity mucous membrane lining,bioadhesive polymer (e.g., polycarbofil, carbopol) may be added. Thecasting includes pouring the solution on a non-adhesive surface,spreading the solution in a uniform thickness (preferably about 10-1000μ) with a coating tool such as doctor blade and the like and drying thesolution to give a film. The film thus formed may be dried at roomtemperature or under heating and cut into a desired surface area.

Examples of preferable oral cavity rapid disintegrator are a solid rapiddiffusing administration agent having a net structure of the compound(aVa), (aVb), (bX), (bXI) or (cVII), or a combination drug and watersoluble or water diffusable carrier which are inert to the compound(aVa), (aVb), (bX), (bXI) or (cVII), or a combination drug. The netstructure can be obtained by sublimation of a solvent from the solidcomposition consisting of a solution obtained by dissolving the compound(aVa), (aVb), (bX), (bXI) or (cVII), or a combination drug in a suitablesolvent.

The oral cavity rapid disintegrator preferably contains, in addition tothe compound (aVa), (aVb), (bX), (bXI) or (cVII), or a combination drug,a matrix forming agent and a secondary component.

Examples of the matrix forming agent include animal proteins orvegetable proteins such as gelatins, dextrins, soybeans, wheat, psylliumseed protein and the like; rubber substances such as gum arabic, guargum, agar, xanthan and the like; polysaccharides; alginic acids;carboxymethylcelluloses; carrageenans; dextrans; pectins; syntheticpolymers such as polyvinylpyrrolidone and the like; a material derivedfrom a gelatin-gum arabic complex and the like. In addition, saccharidessuch as mannitol, dextrose, lactose, galactose, trehalose and the like;cyclic saccharides such as cyclodextrin and the like; inorganic saltssuch as sodium phosphate, sodium chloride, aluminum silicate and thelike; amino acid having 2 to 12 carbon atoms such as glycine, L-alanine,L-aspartic acid, L-glutamine acid, L-hydroxyproline, L-isoleucine,L-leucine, L-phenylalanine and the like are exemplified.

It is possible to introduce one or more matrix forming agents into asolution or suspension before preparation into a solid. Such matrixforming agent may exist with a surfactant or without a surfactant. Thematrix forming agent can form a matrix, and also can help maintain thediffusion of the compound (aVa), (aVb), (bX), (bXI) or (cVII), or acombination drug in the solution or suspension.

The composition may contain a secondary component such as apreservative, an antioxidant, a surfactant, a thickener, a coloringagent, a pH adjusting agent, a flavor, a sweetener, a taste maskingreagent and the like. Examples of a suitable coloring agent include red,black and yellow ferric oxides and FD&C dyes of Ellis & Everard, such asFD&C blue NO. 2, FD&C red No. 40 and the like. A suitable flavorcontains mint, rasberry, licorice, orange, lemon, grapefruit, caramel,vanilla, cherry, grape flavor and a combination of these. Suitable pHadjusting agent includes citric acid, tartaric acid, phosphoric acid,hydrochloric acid and maleic acid. Suitable sweetener includesaspartame, acesulfame K, thaumatin and the like. Suitable taste maskingagent includes sodium bicarbonate, ion exchange resin, cyclodextrininclusion compound, adsorbent substance and microcapsuled apomorphine.

As the preparation, one containing the compound (aVa), (aVb), (bX),(bXI) or (cVII), or a combination drug generally in a proportion ofabout 0.1-about 50 wt %, preferably about 0.1-about 30 wt %, which iscapable of dissolving 90% or more of the compound (aVa), (aVb), (bX),(bXI) or (cVII), or a combination drug in water for about 1 min-about 60min, preferably about 1 min-about 15 min, more preferably about 2min-about 5 min, such as the above-mentioned sublingual tablet, buccaland the like, and an oral cavity rapid disintegrator that disintegrateswithin 1-60 sec, preferably 1-30 sec, more preferably 1-10 sec, afterbeing placed in an oral cavity, are preferable.

The content of the above-mentioned excipient in the whole preparation isabout 10-about 99 wt %, preferably about 30-about 90 wt %. The contentof the β-cyclodextrin or β-cyclodextrin derivative relative to the wholepreparation is 0-about 30 wt %. The content of the lubricant relative tothe whole preparation is about 0.01-about 10 wt %, preferably about1-about 5 wt %. The content of the isotonicity agent relative to thewhole preparation is about 0.1-about 90 wt %, preferably about 10-about70 wt %. The content of the hydrophilic carrier relative to the wholepreparation is about 0.1-about 50 wt %, preferably about 10-about 30 wt%. The content of the water dispersible polymer relative to the wholepreparation is about 0.1-about 30 wt %, preferably about 10-about 25 wt%. The content of the stabilizer relative to the whole preparation isabout 0.1-about 10 wt %, preferably about 1-about 5 wt %. Theabove-mentioned preparation may contain additives such as a coloringagent, a sweetener, an antiseptic and the like as necessary.

While the dose of the combination agent of the present invention variesdepending on the kind of the compound (aVa), (aVb), (bX), (bXI) or(cVII), the patient's age, body weight and condition, the dosage form,the mode and the period of the treatment, the respective amounts of thecompound (aVa), (aVb) (bX), (bXI) or (cVII) and combination drug may be,for example, about 0.01 to about 1000 mg/kg, preferably about 0.01 toabout 100 mg/kg, more preferably about 0.1 to about 100 mg/kg, mostpreferably about 0.1 to about 50 mg/kg, and particularly about 1.5 toabout 30 mg/kg per day, for a patient (adult weighing about 60 kg) with,for example, breast cancer, said daily dose being given intravenouslyonce or in several portions during a day. It is a matter of course thata lower daily dose may be sufficient or an excessive dose may berequired since the dose may vary depending on various factors asdiscussed above.

The combination drug may be contained in any amount as long as a sideeffect does not pose a problem. While the daily dose of the combinationdrug may vary depending on the disease state, age, sex, body weight anddifference in sensitivity of the administration object, timing andinterval of administration, characteristics, dispensing and kind of thepharmaceutical preparation, the kind of the active ingredient and thelike, and is not particularly limited, the amount of the drug isgenerally about 0.001-2000 mg, preferably about 0.01-500 mg, morepreferably about 0.1-100 mg, per 1 kg body weight of mammal by oraladministration, which is generally administered once or in 2 to 4portions during a day.

When the combination agent of the present invention is administered, itmay be administered at the same time. However, a combination drug may beadministered first, and then the compound (aVa), (aVb), (bX), (bXI) or(cVII) may be administered. Alternatively, the compound (aVa), (aVb),(bX), (bXI) or (cVII) may be administered first, and then a combinationdrug may be administered. For time stagger administration, the timedifference varies depending on the active ingredient to be administered,dosage form and administration route. For example, when the combinationdrug is to be administered first, the compound (aVa), (aVb), (bX), (bXI)or (cVII) is administered within 1 min-3 days, preferably 10 min-1 day,more preferably 15 min-1 hour, after the administration of thecombination drug. When the compound (aVa), (aVb), (bX), (bXI) or (cVII)is to be administered first, the combination drug is administered within1 min-1 day, preferably 10 min-6 hours, more preferably 15 min-1 hour,after the administration of the compound (aVa), (aVb), (bX), (bXI) or(cVII).

A preferable administration method includes orally administering about0.001-200 mg/kg of a combination drug prepared into a preparation fororal administration, and about 15 min later, orally administering about0.005-100 mg/kg of the compound (aVa), (aVb), (bX), (bXI) or (cVII)prepared into a preparation for oral administration as an amount for theday.

In addition, the pharmaceutical composition of the present invention orthe combination agent of the present invention may be combined with atherapy without medicine, such as (1) operation, (2) vasopressorchemotherapy using angiotensin II, (3) gene therapy, (4) thermotherapy,(5) cryotherapy, (6) laser cauterization therapy, (7) radiation therapyand the like.

For example, the use of the pharmaceutical composition of the presentinvention or the combination agent of the present invention before orafter operation, or before or after a combined treatment of two or threekinds thereof affords effects such as prevention of expression ofresistance, prolonged Disease-Free Survival time, suppression ofmetastasis or recurrence, life prolonging and the like.

It is also possible to combine a therapy with the pharmaceuticalcomposition of the present invention or the combination agent of thepresent invention, with a supportive therapy such as (i) administrationof antibiotics against complication with various infectious diseases(e.g., β-lactam group such as pansporin, macrolide group such asclarithromycin etc.), (ii) administration of total parenteral nutrition,amino acid preparation, multivitamin preparation for improvement ofmalnutrition, (iii) administration of morphine for relieving pain, (iv)administration of medicine to improve side effects such as nausea,vomition, anorexia, diarrhea, hypoleukocytemia, thrombocytopenia,decreased hemoglobin concentration, alopecia, hepatopathy, nephropathy,DIC., onset of fever and the like, and (v) administration of medicine tosuppress multiple drug resistance in cancer, and the like.

It is preferable that the pharmaceutical composition of the presentinvention or the combination agent of the present invention beadministered before or after the aforementioned treatment by oraladministration (inclusive of sustained release administration),intravenous administration (inclusive of bolus, infusion and inclusioncompound), subcutaneous or intramuscular injection (inclusive of bolus,infusion, sustained release administration), transdermal, intra-tumorand proximal administrations.

When the pharmaceutical composition of the present invention or thecombination agent of the present invention is administered beforeoperation, for example, it may be administered once at about 30 min to24 hours before the operation etc., or may be administered at about 3 to6 months before the operation etc. in 1 to 3 cycles. The administrationof the pharmaceutical composition of the present invention or thecombination agent of the present invention before operation decreasessize of, for example, cancer tissues, thereby facilitating the operationetc.

When the pharmaceutical composition of the present invention or thecombination agent of the present invention is administered afteroperation, for example, it may be repeat administered at about 30 min to24 hours after the operation etc. for several weeks to 3 months. Theadministration of the pharmaceutical composition of the presentinvention or the combination agent of the present invention afteroperation enhances the effect of the operation.

EXAMPLES

While the present invention is explained in detail in the following byreferring to Reference Examples and Examples, the present invention isnot limited by these Examples.

The abbreviations used in the description mean the following.

s: singlet

d: doublet

t: triplet

m: multiplet

J: coupling constant

Hz: Hertz

CDCl₃: Deuterated Chloroform

DMSO-d₆: Deuterated dimethyl sulfoxide

D₂O: deuterium oxide

¹H-NMR: protone nuclear magnetic resonance

HPLC: high performance liquid chromatography

Me: methyl

Room Temperature: 15 to 30° C.

¹H-NMR spectrum was measured by Bruker DPX 300 (300 MHz) typeSpectrometer using tetramethylsilane as an internal standard. All δvalues are shown in ppm.

HPLC Conditions in Example 4

column: Inertsil (trademark) ODS-3 (4.6×150 mm I.D.) (GL Science Inc.)

mobile phase: 0.05M potassium dihydrogen phosphate /acetonitrile=45/55

wavelength: 254 nm

temperature: 25° C.

flow: 1 ml/min

HPLC conditions in Reference Example 12, Example 21 and Example 22

column: YMC-Pack ODS-A A-302(150×4.6 mm I.D.) (trademark, YMC Co., Ltd)

mobile phase: 0.05M potassium dihydrogen phosphate/acetonitrile=45/55

wavelength: 270 nm

temperature: 25° C.

Flow: 1 ml/min

Powder X ray diffraction was measured using X-ray Diffractometer RINTUltima+(Rigaku).

Reference Example 1

Production of 4-chloro-1-(4-methoxyphenyl)-1-butanone

Anisole (6.75 g, 62.4 mmol) was dissolved in dichloromethane (80 ml).The mixture was cooled to −5° C. and aluminum chloride (8.32 g, 62.4mmol) was added. 4-Chlorobutyryl chloride (8.8 g, 62.4 mmol) was addeddropwise to the mixture at −10° C. and stirred at −10° C. for 1 hour.The reaction mixture was poured into iced water (100 ml). Afterseparation, the organic layer was washed with 1N hydrochloric acid (50ml), saturated aqueous sodium hydrogen carbonate (50 ml) and water (50ml), and was concentrated under reduced pressure to give4-chloro-1-(4-methoxyphenyl)-1-butanone (12.7 g).

yield 96%.

¹H-NMR (CDCl₃, δ, 300 MHz) 2.19-2.24(2H,m), 3.13(2H,t,J=7.0 Hz),3.67(2H,t,J=6.2 Hz), 3.87(3H,s), 6.92-6.96(2H,m), 7.94-7.98(2H,m).

Reference Example 2

Production of 4-chloro-1-(4-methoxyphenyl)-1-butanone

Anisole (2.16 g, 20 mmol) was dissolved in toluene (20 ml). The mixturewas cooled to −10° C. and aluminum chloride (2.67 g, 20 mmol) was added.4-Chlorobutyryl chloride (2.47 ml, 22 mmol) was added dropwise at −10°C. and stirred for 0.5 hour at −10° C. The reaction mixture was pouredinto iced water (40 ml). After separation, the organic layer was washedwith 20%citric acid (10 ml) twice, 1N-sodium hydroxide (10 ml) and 20%brine (10 ml) twice, and was concentrated under reduced pressure to give4-chloro-1-(4-methoxyphenyl)-1-butanone (4.21 g, yield 99%).

Reference Example 3

Production of 1-(4-chlorobutyl)-4-methoxybenzene

4-Chloro-1-(4-methoxyphenyl)-1-butanone (5 g, 23.5 mmol) was dissolvedin tetrahydrofuran (50 ml). 10% Palladium carbon (water-containingproduct, 500 mg) was added and the mixture was subjected to catalyticreduction under hydrogen pressure (0.8 MPa, 50° C. for 3 h). Thecatalyst was filtered off and the filtrate was concentrated underreduced pressure to give 1-(4-chlorobutyl)-4-methoxybenzene (4.6 g,yield 99%).

¹H-NMR (CDCl₃, δ, 300 MHz) 1.69-1.83(4H,m), 2.59(2H,t,J=7.4 Hz),3.54(2H,t,J=6.2 Hz), 3.79(3H,s), 6.81-6.85(2H,m), 7.08-7.11(2H,m).

EXAMPLE 1

Production of 1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazolemethanesulfonate

1-(4-Chlorobutyl)-4-methoxybenzene (950 mg, 4.78 mmol),1H-1,2,3-triazole (660 mg, 9.55 mmol) and potassium iodide (793 mg, 4.78mmol) were added to t-butanol (5 ml). Sodium hydroxide (382 mg, 9.55mmol) was added and the mixture was refluxed under heating for 11 hours.After cooling to room temperature, toluene and water were added and themixture was partitioned. The organic layer was washed successively withwater, 20% citric acid, saturated aqueous sodium hydrogen carbonate andwater, and was concentrated under reduced pressure. To the residue wereadded ethyl acetate (6 ml) and isopropyl ether (3 ml). Methanesulfonicacid (402 mg, 4.18 mmol) was added at room temperature. Ethylacetate/isopropyl ether=2/1 (2 ml) was added and the mixture was stirredat room temperature for 30 min. The precipitated crystals were collectedby filtration and dried under reduced pressure to give1-[4-(4-methoxyphenyl)-butan-1-yl]-1H-1,2,3-triazole methanesulfonate(1.14 g, yield 73%).

¹H-NMR (DMSO-d₆, δ, 300 MHz) 1.40-1.51(2H,m), 1.74-1.84(2H,m)2.39(3H,s), 2.51(2H,t,J=7.7 Hz), 3.69(3H,s), 4.38(2H,t,J=7.0 Hz),6.79-6.84(2H,m), 7.04-7.09(2H,m), 7.71(1H,d,J=0.7 Hz), 8.11(1H,d,J=0.7Hz).

EXAMPLE 2

Production of 1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazolemethanesulfonate

To 1-(4-Chlorobutyl)-4-methoxybenzene (2468 mg, 12.42 mmol) was added2-methyl-2-butanol (5 ml), and then 1H-1,2,3-triazole (1286 mg, 18.62mmol) and potassium iodide (2062 mg, 14.24 mmol) were added. Sodiumhydroxide (745 mg, 18.62 mmol) was added and the mixture was refluxedunder heating for 4 hours. After cooling to room temperature, tolueneand water were added and the mixture was partitioned. The organic layerwas washed with water, 20%citric acid (twice), saturated aqueous sodiumhydrogen carbonate and water (twice). The organic layer was concentratedunder reduced pressure. To the residue was added ethyl acetate and themixture was concentrated under reduced pressure. Ethyl acetate (20 ml)and isopropyl ether (10 ml) were added and then seed crystal was added.Methanesulfonic acid (1021 mg, 10.62 mmol) was added dropwise whilekeeping the mixture at 20-30° C. The mixture was stirred at 20-30° C.for 1 hour. The precipitated crystals were collected by filtration andwashed with ethyl acetate/isopropyl ether=1/1. The crystals were driedunder reduced pressure to give1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole methanesulfonate(3.04 g) as white crystals (yield 75%).

¹H-NMR (DMSO-d₆, δ, 300 MHz) 1.40-1.51(2H,m), 1.74-1.84(2H,m)2.39(3H,s), 2.51(2H,t,J=7.7 Hz), 3.69(3H,s), 4.38(2H,t,J=7.0 Hz),6.79-6.84(2H,m), 7.04-7.09(2H,m), 7.71(1H,d,J=0.7 Hz), 8.11(1H,d,J=0.7Hz)

EXAMPLE 3

Production of 1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazolehydrochloride

1-(4-Chlorobutyl)-4-methoxybenzene (993 mg, 5 mmol), 1H-1,2,3-triazole(691 mg, 10 mmol), potassium iodide (830 mg, 5 mmol) and lithiumchloride (424 mg, 10 mmol) were added to t-butanol (5 ml), andt-butoxysodium (961 mg, 10 mmol) was added. The mixture was refluxedunder heating for 17 hours. After cooling to room temperature, tolueneand water were added and the mixture was partitioned. The organic layerwas washed with water, 20% citric acid (three times), saturated aqueoussodium hydrogen carbonate and water, and concentrated under reducedpressure. To the residue was added ethanol (30 ml). Concentratedhydrochloric acid (2 ml) was added and the mixture was concentratedunder reduced pressure. To the residue was added 2-propanol, and afterconcentration under reduced pressure, ethyl acetate was added. Themixture was concentrated under reduced pressure and ethyl acetate (3 ml)was added. The mixture was stirred at room temperature for 45 min. Theprecipitated crystals were collected by filtration and dried underreduced pressure to give1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole hydrochloride (772mg, yield 58%).

¹H-NMR (DMSO-d₆, δ, 300 MHz) 1.39-1.50(2H,m), 1.73-1.83(2H,m)2.49(2H,t,J=7.6 Hz), 3.68(3H,s), 4.37(2H,t,J=7.0 Hz), 6.77-6.83(2H,m),7.02-7.07(2H,m), 7.73(1H,d,J=0.7 Hz), 8.13(1H,d,J=0.7 Hz).

EXAMPLE 4

Production of 1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole

1-(4-Chlorobutyl)-4-methoxybenzene (993 mg, 5 mmol), 1H-1,2,3-triazole(691 mg, 10 mmol) and potassium iodide (830 mg, 5.0 mmol) were dissolvedin dimethylformamide (5 ml) and the mixture was stirred at 100° C. for2.5 hours. After cooling the reaction mixture to room temperature, ethylacetate and water were added, and the mixture was partitioned. Theorganic layer was measured by HPLC. As a result,1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole (550 mg) was foundto be present (yield 48%).

Reference Example 4

Production of 4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol

1-[4-(4-Methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole methanesulfonate(4.0 g, 12.22 mmol) was added into 48% hydrobromic acid (8 ml) and themixture was heated at 80-90° C. for 6 hours. The reaction mixture wasice-cooled and 4N-sodium hydroxide (32 ml) was added dropwise. Themixture was washed with toluene. 6N Hydrochloric acid was added to theaqueous layer to adjust pH to 6.3. The mixture was extracted with ethylacetate (30 ml) and tetrahydrofuran (15 ml) and then washed with water.Activated carbon (200 mg) was added and the mixture was stirred at roomtemperature for 10 min. The mixture was filtrated and concentrated underreduced pressure. To the residue was added ethyl acetate (10 ml), andthe mixture was refluxed. After allowing to cool and stirring for 30min, hexane (10 ml) was added and the mixture was stirred at roomtemperature for 30 min. The precipitated crystals were collected byfiltration and dried under reduced pressure to give4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol (2.25 g, yield 85%).

¹H-NMR (CDCl₃-DMSO-d₆, δ, 300 MHz) 1.48-1.59(2H,m), 1.80-1.91(2H,m),2.49(2H,t,J=7.5 Hz), 4.31(2H,t,J=7.2 Hz), 6.68-6.73(2H,m),6.87-6.91(2H,m), 7.45(1H,d,J=0.7 Hz), 7.61(1H,d,J=0.7 Hz), 8.12(1H,s).

Reference Example 5

Production of 4-(trifluoromethyl)cinnamamide

4-(Trifluoromethyl)cinnamic acid (64.85 g, 300 mmol) was added totoluene (325 ml) and dimethylformamide (2.2 ml). Thionyl chloride (26.3ml, 361 mmol) was added dropwise at room temperature. The mixture washeated at 45° C. for 2 hours. The obtained reaction mixture was addeddropwise to 25% aqueous ammonia (325 ml) while keeping the mixture at5-20° C. The mixture was stirred at room temperature for 1 hour. Thecrystals were filtered, washed with water and isopropyl ether and driedunder reduced pressure to give 4-(trifluoromethyl)-cinnamamide (60.76 g,yield 94%). H-NMR (CDCl₃-DMSO-d₆, δ, 300 MHz) 5.93(1H,s),6.53(1H,d,J=15.8 Hz), 6.75(1H,s), 7.48-7.53(5H,m).

Reference Example 6

Production of4-(chloromethyl)-2-[(E)-2-[4-(trifluoromethyl)-phenyl]ethenyl]-1,3-oxazole

4-(Trifluoromethyl)cinnamamide (1 g, 4.65 mmol) and 1,3-dichloroacetone(1.1 g, 8.66 mmol) were added to toluene (5 ml) and the mixture wasrefluxed under heating for 8 hours. Ethyl acetate (20 ml) was added andthe mixture was washed with water (20 ml) twice, and then concentratedunder reduced pressure. To the residue was added methanol (4 ml) and themixture was stirred at room temperature. The crystals were filtrated anddried under reduced pressure to give4-(chloromethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole(733 mg, yield 55%).

¹H-NMR (CDCl₃, δ, 300 MHz) 4.56(2H,s), 7.01(1H,d,J=16.4 Hz),7.54-7.68(6H,m).

Reference Example 7

Production of1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole

4-[4-(1H-1,2,3-Triazol-1-yl)butyl]phenol (400 mg, 1.84 mmol) and4-(chloromethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole(529 mg, 1.84 mmol) were dissolved in dimethylformamide (3 ml) andpotassium carbonate (279 mg, 2.02 mmol) was added. The mixture wasstirred at 65-75° C. for 4 hours.4-[4-(1H-1,2,3-Triazol-1-yl)butyl]phenol (40 mg, 0.184 mmol) was addedand the mixture was stirred at 65-75° C. for further 3 hours. Themixture was cooled to room temperature and water (5 ml) was added, thenmethanol (3 ml) was added. The mixture was stirred at room temperaturefor 40 min, and the precipitated crystals were collected by filtrationand washed with water. The crystals were dried under reduced pressure togive1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole(799 mg, yield 93%).

¹H-NMR (CDCl₃, δ, 300 MHz) 1.57-1.68(2H,m), 1.88-1.99(2H,m),2.60(2H,t,J=7.5 Hz), 4.39(2H,t,J=7.-1 Hz), 5.01(2H,s), 6.89-7.08(5H,m),7.49-7.70(8H,m).

EXAMPLE 5

Production of 4-[4-(tert-butoxy)phenyl]butyl methanesulfonate

To the kolben were added 4-[4-(tert-butoxy)phenyl]butyl methanesulfonate(33.66 g), sodium iodide (22.49 g) and acetone (337 ml), and the mixturewas reacted for 1 hour by reflux under heating. To the reaction mixturewere added water (500 ml) and diisopropyl ether (500 ml). Afterstirring, the mixture was left standing and partitioned to separate theorganic layer. The organic layer was washed successively with saturatedaqueous sodium hydrogen carbonate (250 ml), 10% solution of Na₂S₂O₃ (250ml) twice and water (250 ml). The organic layer was concentrated underreduced pressure to give the objective compound (35.8 g) as aconcentrated residue.

¹H-NMR (CDCl₃, 300 MHz) ppm: 1.33(9H,s), 1.6-1,8(4H,m), 2.62(2H, t,J=7.1), 2.99(3H,s), 4.24(2H,t,J=6.1), 6.91(2H,d,J=8.5 Hz),7.05(2H,d,J=8.5 Hz)

Reference Example 8

Production of 1-tert-butoxy-4-(4-iodobutyl)benzene

To the kolben were added 4-[4-(tert-butoxy)phenyl]butyl methanesulfonate(33.66 g), sodium iodide (22.49 g) and acetone (337 ml), and the mixturewas reacted for 1 hour by reflux under heating. To the reaction mixturewere added water (500 ml) and diisopropyl ether (500 ml). Afterstirring, the mixture was left standing and partitioned to separate theorganic layer. The organic layer was washed successively with saturatedaqueous sodium hydrogen carbonate (250 ml), 10% hypo (250 ml) twice andwater (250 ml). The organic layer was concentrated under reducedpressure to give the objective compound (35.8 g) as a concentratedresidue.

¹H-NMR (CDCl_(3, 300) MHz) ppm: 1.33(9H,s), 1.6-1.7(2H,m),1,8-1.9(2H,m), 2.59(2H,t,J=7.5 Hz), 3.20(2H,t,J=6.9 Hz), 6.90(2H,d,J=8.4Hz), 7.04(2H,d,J=8.4 Hz)

EXAMPLE 6

Production of 4-[4-(tert-butoxy)phenyl]butyl (4-methylbenzene)-sulfonate

To the kolben were added 4-[4-(tert-butoxy)phenyl-butan-1-ol (5.28 g)and pyridine (9 ml), and the mixture was stirred. Toluenesulfonylchloride (5.70 g, 1.5 eq) was added at an inner temperature of 5° C. andthe mixture was allowed to react at room temperature for 2 hours. Water(20 ml) was added at not higher than 10° C. and the mixture was stirredfor 5 min. Ethyl acetate (40 ml) was added and the aqueous layer wasseparated. The organic layer was washed with 10% aqueous boric acid (20ml) three times and with water (20 ml) once. The organic layer wasconcentrated under reduced pressure to give a concentrated residue (8.80g) of the objective compound.

This was applied to silica gel chromatography and the effective fractionwas concentrated to give the objective compound (6.40 g).

¹H-NMR (CDCl₃, 300 MHz) ppm: 1.32(9H,s), 1.5-1.7(4H,m), 2.45(3H,s),2.52(2H,t,J=7.-1 Hz), 4.04(2H,t,J=6.0 Hz), 6.87(2H,d,J=8.5 Hz),6.98(2H,d,J=8.5 Hz), 7.33(2H,d,J=8.1 Hz), 7.78(2H,d,J=8.1 Hz)

EXAMPLE 7

Production of 1-tert-butoxy-4-(4-chlorobutyl)benzene

To a solution of 4-[4-(tert-butoxy)phenyl-butan-1-ol (44.7 g), toluene(220 ml) and triethylamine (30.4 g) was added dropwise thionyl chloride(28.6 g) at an inner temperature 60° C. over about 2 hours, and themixture was reacted for 4 hours. Water (90 ml) was added to separate theorganic layer. The organic layer was washed with 5% sodium hydrogencarbonate (90 ml) and water (90 ml), and dried over anhydrous magnesiumsulfate. The organic layer was concentrated and evaporated under reducedpressure (128-130° C./0.2 mmHg) to give the objective compound (34.3 g).

1H-NMR (CDCl₃, 300 MHz) ppm: 1.32(9H,s), 1.7-1.8(4H,m), 2.60(2H,t,J=7.2Hz), 3.55(2H,t,J=6.2), 6.90(2H,d,J=8.4 Hz), 7.06(2H,d,J=8.4 Hz)

EXAMPLE 8

Production of 1-tert-butoxy-4-(4-chlorobutyl)benzene

To the kolben were added 4-[4-(tert-butoxy)phenyl-butan-1-ol (5.0 g) andpyridine (15 ml), and the mixture was stirred. To the mixture was addeddropwise methanesulfonyl chloride (3.84 g) under ice-cooling. Themixture was heated to about 60° C. and reacted for 2 hours. To thereaction mixture were added toluene (25 ml) and water (25 ml), and themixture was stirred, left standing and partitioned. The organic layerwas washed with water (25 ml) twice. The organic layer was concentratedto give the objective compound (4.27 g) as a concentrated residue.

EXAMPLE 9

Production of 1-[4-(4-tert-butoxyphenyl)butan-1-yl]-1H-1,2,3-triazole

To the kolben were added 1H-1,2,3-triazole (5.18 g), sodium iodide (7.49g), sodium hydroxide (3.0 g) and 2-methyl-2-butanol (20 ml), and themixture was refluxed under heating for 1 hour (inner temperature thenwas 100-102° C.). A solution of 4-[4-(tert-butoxy)phenyl]butylmethanesulfonate (15.09 g)/2-methyl-2-butanol (20 ml) was added dropwiseover about 1 hour 40 min. The mixture was reacted at the sametemperature for 3 hours. After cooling, the mixture was concentrated. Tothe residue were added water (20 ml) and toluene (20 ml), and themixture was stirred. After standing and partitioning, the organic layerwas washed with 5% aqueous sodium hydrogen carbonate (20 ml) and thenwith water (20 ml). The organic layer was concentrated to give objectivecompound (12.72 g) as a concentrated residue.

¹H-NMR (CDCl₃, 300 MHz) ppm :1.35(9H,s), 1.6-1.7(2H,m), 1.9-2.0(2H,m),2.63(2H,t,J=7.6 Hz), 4.41(2H,t,J=7.-1 Hz), 6.91(2H,d,J=8.5 Hz),7.04(2H,d,J=8.5),7.51(1H,d,J=0.8), 7.71(1H,d,J=0.8)

EXAMPLE 10

Production of 1-[4-(4-tert-butoxyphenyl)butan-1-yl]-1H-1,2,3-triazole

To the kolben were added sodium hydroxide (3.0 g), 1H-1,2,3-triazole(5.18 g) and 2-methyl-2-butanol (20 ml), and the mixture was refluxedunder heating for 1 hour (inner temperature then was 100-102° C.). Asolution of 1-tert-butoxy-4-(4-iodobutyl)benzene (17.9g)/2-methyl-2-butanol (20 ml) was added dropwise over about 1 hour 50min. The mixture was reacted at the same temperature for 3 hours. Aftercooling, the mixture was concentrated. To the residue were added water(20 ml) and toluene (20 ml), and the mixture was stirred. After standingand partitioning, the organic layer was washed with 5% aqueous sodiumhydrogen carbonate (20 ml) and then with water (20 ml). The organiclayer was concentrated to give objective compound (15.6 g) as aconcentrated residue.

EXAMPLE 11

Production of 1-[4-(4-tert-butoxyphenyl)butan-1-yl]-1H-1,2,3-triazole

To the kolben were added 1H-1,2,3-triazole (1.65 g), sodium iodide (3.58g), sodium hydroxide (0.96 g) and 2-methyl-2-butanol (7 ml), and themixture was refluxed under heating for 1 hour (inner temperature thenwas 100-102°C.). A solution of 4-[4-(tert-butoxy)phenyl]butyl(4-methylbenzene)sulfonate (6.00 g)/2-methyt-2-butanol (7 ml) was addeddropwise over about 1 hour. The mixture was reacted at the sametemperature for 3 hours. After cooling, the mixture was concentrated. Tothe residue were added water (10 ml) and toluene (20 ml), and themixture was stirred. After standing and partitioning, the organic layerwas washed with 5% aqueous sodium hydrogen carbonate (10 ml) and thenwith water (10 ml). The organic layer was concentrated to give objectivecompound (4.10 g) as concentrated residue.

EXAMPLE 12

Production of 1-[4-(4-tert-butoxyphenyl)butan-1-yl]-1H-1,2,3-triazole

To the kolben were added 1H-1,2,3-triazole (5,18 g), sodium iodide (7.48g), sodium hydroxide (3.0 g) and 2-methyl-2-butanol (20 ml), and themixture was refluxed under heating for 1 hour. A solution of1-tert-butoxy-4-(4-chlorobutyl)benzene (12.04 g)/2-methyl-2-butanol (20ml) was added dropwise over about 2 hours, and the mixture was reactedat inner temperature 100-102° C. for 2 hours. Water (20 ml) and toluene(20 ml) was added and the mixture was stirred, left standing andpartitioned to separate the aqueous layer. The organic layer was washedsuccessively with 5% aqueous sodium hydrogen carbonate (20 ml) and water(20 ml). The organic layer was concentrated to give the objectivecompound (13.55 g) as a concentrated residue.

Reference Example 9

Production of 4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol

To the kolben were added1-[4-(4-tert-butoxyphenyl)butan-1-yl]-1H-1,2,3-triazole (10.0 g) and4N-hydrochloric acid (40 ml), and the mixture was reacted at 49-52° C.for 1 hour. After completion of the reaction, 30% sodium hydroxide (18ml) was added and the mixture was extracted with ethyl acetate (100 ml).The organic layer was washed with 5% aqueous sodium hydrogen carbonate(50 ml) and water (50 ml), and the organic layer was concentrated todryness. To the concentrated residue was added ethyl acetate (15 ml) andthe mixture was refluxed under heating for about 30 min. The mixture wasallowed to cool with stirring for 1 hour, and stirred at 5-10° C. for 1hour. The precipitated crystals were collected by filtration and washedwith cold-ethyl acetate (2.5 ml).

Wet crystals were dried under reduced pressure at an outer temperatureof 40° C. to give 4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol (5.51 g).

Reference Example 10

Production of 4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol

To the kolben were added1-[4-(4-tert-butoxyphenyl)butan-1-yl]-1H-1,2,3-triazole (10.0 g) and4N-hydrochloric acid (40 ml), and the mixture was heated to about 50° C.and reacted for 1 hour. The reaction mixture was adjusted to pH 2.5 with30% aqueous sodium hydroxide, and extracted with ethyl acetate (140 ml).The organic layer was washed successively with saturated sodium hydrogencarbonate (50 ml) and water (50 ml), and the organic layer wasconcentrated. To the residue was added ethyl acetate (20 ml) and themixture was heated under reflux to dissolve the residue, which was thenallowed to cool to allow crystallization. The mixture was cooled toabout 5° C. and stirred for 1 hour. The precipitated crystals werecollected by filtration and washed with cold-ethyl acetate (25 ml). Wetcrystals were dried to give the objective compound (6.14 g).

EXAMPLE 13

Production of 1-(4-phenylbutyl)-1H-1,2,3-triazole

1,2,3-Triazole (1623 mg, 23.5 mmol), sodium iodide (2353 mg, 15.7 mmol)and sodium hydroxide (940 mg, 23.5 mmol) were added to t-amyl alcohol(6.2 ml), and the mixture was refluxed under stirring for 1 hour.1-Chloro-4-phenylbutane (2648 mg, 15.7 mmol) was dissolved in t-amylalcohol (6.2 ml) and added dropwise under reflux over 1 hour. Themixture was refluxed under stirring for 2 hours and cooled to roomtemperature, and toluene (50 ml) was added. The mixture was washed withwater (50 ml×2), dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=4/1→1/3) to give1-(4-phenylbutyl)-1H-1,2,3-triazole (2.56 g) as colorless oil. yield81%. 2-(4-Phenylbutyl)-2H-1,2,3-triazole (360 mg) was obtained as acolorless oil (yield 11%). 1-(4-phenylbutyl)-1H-1,2,3-triazole

¹H-NMR (CDCl₃, δ, 300 MHz) 1.59-1.70(2H,m), 1.87-2.00(2H,m),2.65(2H,t,J=7.54 Hz), 4.39(2H,t,J=7.12 Hz), 7.12-7.30(5H,m), 7.50(1H,s),7.69(1H,s) 2-(4-phenylbutyl)-2H-1,2,3-triazole

¹H-NMR (CDCl₃, δ, 300 MHz) 1.58-1.67(2H,m), 1.96-2.07(2H,m)2.65(2H,t,J=7.63 Hz), 4.47(2H,t,J=7.04 Hz), 7.13-7.30(5H,m), 7.59(2H,s).

EXAMPLE 14

Production of 1-(2-phenylethyl)-1H-1,2,3-triazole

1,2,3-Triazole (1634 mg, 23.7 mmol), sodium iodide (2364 mg, 15.8 mmol),sodium hydroxide (946 mg, 23.7 mmol) were added to t-amyl alcohol (6.2ml), and the mixture was refluxed under stirring for 1 hour.1-Chloro-2-phenylethane (2217 mg, 15.8 mmol) was dissolved in t-amylalcohol (6.2 ml) and added dropwise under reflux over 1 hour. Themixture was refluxed under stirring for 3.5 hours. The mixture wascooled to room temperature and toluene (50 ml) was added. The mixturewas washed with water (50×2), dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=3/1→1/3) to give1-(2-phenylethyl)-1H-1,2,3-triazole as a colorless oil (2.0 g, yield73%). 2-(2-Phenylethyl)-2H-1,2,3-triazole (315 mg) was obtained as acolorless oil (yield 12%). 1-(4-phenylethyl)-1H-1,2,3-triazole

¹H-NMR (CDCl₃, δ, 300 MHz) 3.32(2H,t,J=7.20 Hz), 4.62(2H,t,J=7.17 Hz),7.07-7.11(2H,m), 7.21-7.32(4H,m), 7.61(1H,s).2-(4-phenylethyl)-2H-1,2,3-triazole

¹H-NMR (CDCl₃, δ, 300 MHz) 3.28(2H,t,J=7.79 Hz) 4.68(2H,t,J=7.60 Hz),7.15-7.32(5H,m), 7.59(2H,s).

EXAMPLE 15

Production of 1-phenyl-2-(1H-1,2,3-triazol-1-yl)ethanone

1,2,3-Triazole (1689 mg, 24.45 mmol), sodium iodide (2443 mg, 16.3 mmol)and sodium hydroxide (978 mg, 24.45 mmol) were added to t-amyl alcohol(6.5 ml), and the mixture was refluxed under stirring for 1 hour.2-Chloro-1-phenylethanone (2520 mg, 16.3 mmol) was dissolved in t-amylalcohol (13 ml) and added dropwise over 1 hour. The mixture was refluxedunder stirring for 1 hour. The mixture was cooled to room temperature,toluene (50 ml) was added. The mixture was washed with water (50 ml×2),dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate=3/2→1/4) to give1-phenyl-2-(1H-1,2,3-triazol-1-yl)ethanone (1.38 g) as brown crystals(yield 45%). 1-Phenyl-2-(2H-1,2,3-triazol-2-yl)ethanone (550 mg) wasobtained as yellow crystals (yield 18%).1-phenyl-2-(1H-1,2,3-triazol-1-yl)ethanone

¹H-NMR (CDCl₃, δ, 300 MHz) 5.91(2H,s), 7.52-7.58(2H,m), 7.65-7.69(1H,m),7.74(1H,d,J=0.95 Hz), 7.80(1H,d,J=0.95 Hz), 7.99-8.03(2H,m).1-phenyl-2-(2H-1,2,3-triazol-2-yl)ethanone

¹H-NMR (CDCl₃, δ, 300 MHz) 5.92(2H,s), 7.49-7.55(2H,m), 7.62-7.66(1H,m),7.74(2H,s), 7.95-7.99(2H,m).

EXAMPLE 16

Production of 1-benzyl-1H-1,2,3-triazole

1,2,3-Triazole (1523 mg, 22.05 mmol), sodium iodide (2203 mg, 14.7 mmol)and sodium hydroxide (882 mg, 22.05 mmol) were added to t-amyl alcohol(5.8 ml), and the mixture was refluxed under stirring for 1 hour. Benzylchloride (1861 mg, 14.7 mmol) was dissolved in t-amyl alcohol (5.8 ml)and added dropwise under reflux over 1 hour. The mixture was refluxedunder stirring for 1 hour. The mixture was cooled to room temperatureand toluene (50 ml) was added. The mixture was washed with water (50×2),dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate=3/1→1/3) to give 1-benzyl-1H-1,2,3-triazole (2.10g) as white crystals, yield 90%, and 2-benzyl-2H-1,2,3-triazole (140 mg)as white crystals (yield 6%). 1-benzyl-1H-1,2,3-triazole

¹H-NMR (CDCl₃, δ, 300 MHz) 5.56(2H,s), 7.24-7.28(2H, m),7.33-7.40(3H,m), 7.47(1H,s),7.70(1H,s). 2-benzyl-2H-1,2,3-triazole

¹H-NMR (CDCl₃, δ, 300 MHz) 5.61(2H,s), 7.26-7.35(5H, m), 7.63(2H,s).

EXAMPLE 17

Production of 1-(1-naphthylmethyl)-1H-1,2,3-triazole

1,2,3-Triazole (1454 mg, 21.05 mmol), sodium iodide (2103 mg, 14.03mmol) and sodium hydroxide (842 mg, 21.05 mmol) were added to t-amylalcohol (5.5 ml), and the mixture was refluxed under stirring for 1hour. 1-(Chloromethyl)naphthalene (2478 mg, 14.03 mmol) was dissolved int-amyl alcohol (5.5 ml) and added dropwise under reflux over 1 hour. Themixture was refluxed under stirring for 1 hour. The mixture was cooledto room temperature and toluene (50 ml) was added. The mixture waswashed with water (50 ml×2), dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=2/1→1/3) to give1-(1-naphthylmethyl)-1H-1,2,3-triazole (2.47 g) as white crystals (yield84%), and 2-(1-naphthylmethyl)-2H-1,2,3-triazole as a colorless oil (136mg, yield 5%). 1-(1-naphthylmethyl)-1H-1,2,3-triazole

¹H-NMR (CDCl₃, δ, 300 MHz) 6.02(2H,s), 7.33(1H,s), 7.41-7.55(4H,m),7.64(1H,s), 7.89-7.97(3H,m). 2-(1-naphthylmethyl)-2H-1,2,3-triazole

¹H-NMR (CDCl₃, δ, 300 MHz) 6.06(2H,s),7.41-7.57(4H,m), 7.62(2H,s),7.84-7.89(2H,m), 8.15(1H,d,J=7.96 Hz).

Reference Example 11

Production of 2,2-dichloroacetaldehyde tosylhydrazone

Tosylhydrazine (234 g, 1.26 mol) was suspended in propionic acid (2 L)and dichloroacetaldehyde (142 g, 1.26 mol) was added at 15-20° C. Themixture was stirred at room temperature for 2 hours and underice-cooling for 3 hours. The precipitated crystals were collected byfiltration and washed with toluene. The crystals were dried underreduced pressure to give 2,2-dichloroacetaldehyde tosylhydrazone (247 g,yield 70%).

¹H-NMR (CDCl₃, δ, 300 MHz) 2.47(3H,s), 6.12(1H,d,J=7.4 Hz),7.21(1H,d,J=7.4 Hz), 7.34-7.38(2H,m), 7.80-7.84(2H,m), 8.06(1H,s).

Reference Example 12

Production of 1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole

1-(4-Aminobutyl)-4-methoxybenzene hydrochloride (1.0 g, 4.64 mmol) wasdissolved in water. Toluene and 2N-sodium hydroxide (10 ml) were addedand the mixture was partitioned. The mixture was washed with 20% brine,dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was dissolved in methanol (8 ml) and thesuspension of 2,2-dichloroacetaldehyde tosylhydrazone (2.61 g, 9.28mmol) in methanol (12 ml) was added dropwise at 15-20° C., and themixture was stirred at room temperature for 2 hours. Methanol was addedand, after making the mixture homogeneous, it was quantitativelymeasured by HPLC. As a result,1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole (270 mg) was foundto be present.

yield (quantitatively measured) 25%.

EXAMPLE 18

Production of 4-amino-4′-methoxybutyrophenone trifluoromethanesulfonate

Trifluoromethanesulfonic acid (4 ml) was ice-cooled, and 4-aminobutyricacid (1093 mg, 10.6 mmol) was added. Then, anisole (1 ml, 9.25 mmol) wasadded. The mixture was heated and stirred at 80° C. for 50 min. Themixture was cooled to room temperature and added dropwise to water (17ml) under ice-cooling. The mixture was stirred under ice-cooling for 20min and then at −10° C. for 30 min. The crystals were filtrated, washedwith ice-cooled saturated brine, and dried under reduced pressure togive 4-amino-4′-methoxybutyrophenone trifluoromethanesulfonate (2.47 g,yield 78%).

¹H-NMR (D₂O, δ, 300 MHz) 1.88-1.99(2H,m), 2.98(2H,t,J=7.5 Hz),3.09(2H,t,J=7.1 Hz), 3.80(3H,s), 6.95-6.99(2H,m), 7.86-7.91(2H,m).

EXAMPLE 19

Production of 1-(4-aminobutyl)-4-methoxybenzene hydrochloride

4-Amino-4′-methoxybutyrophenone trifluoromethanesulfonate (60 g, 174.8mmol) was dissolved in tetrahydrofuran/water-1/1 (600 ml) and 10%palladium carbon (water-containing product, 6 g) was added. The mixturewas subjected to catalytic reduction at 50° C. for 7 hours underhydrogen pressure (0.8 Mpa). The catalyst was filtered off and toluene(360 ml) and 2N-potassium hydroxide (180 ml) were added. The mixture waspartitioned and the aqueous layer was extracted with toluene (360 ml).The organic layers were combined and washed with 20% brine (3 times). Tothe residue obtained by concentration under reduced pressure was added2-propanol (300 ml) and con. hydrochloric acid (34 ml) was addeddropwise under ice-cooling. To the residue obtained by concentrationunder reduced pressure was added 2-propanol (300 ml) and the mixture wasconcentrated under reduced pressure. 2-Propanol (300 ml) was added andthe mixture was concentrated under reduced pressure. To the obtainedresidue was added isopropyl ether (200 ml) and the mixture was stirredat room temperature for 10 min. The precipitated crystals were collectedby filtration and dried under reduced pressure to give1-(4-aminobutyl)-4-methoxybenzene hydrochloride (32.1 g, yield 85%).

¹H-NMR (D₂O, δ, 300 MHz) 1.54-1.57(4H,m), 2.52(2H,t,J=6.5 Hz),2.89(2H,t,J=6.8 Hz), 3.71(3H,s), 6.85-6.88(2H,m), 7.12-7.15(2H,m).

EXAMPLE 20

Production of 1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole

1-(4-Aminobutyl)-4-methoxybenzene hydrochloride (1.0 g, 4.64 mmol) wasdissolved in water. Toluene (10 ml) and 2N-sodium hydroxide (10 ml) wereadded and the mixture was partitioned. The organic layer was washed with20% brine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was dissolved in methanol (8 ml), and asuspension of 2,2-dichloroacetaldehyde tosylhydrazone (2.61 g, 9.28mmol) in methanol (12 ml) was added dropwise at 15-20° C. The mixturewas stirred at room temperature for 2 hours and concentrated underreduced pressure. To the residue was added ethyl acetate (50 ml) andthen was added saturated aqueous sodium hydrogen carbonate (50 ml). Themixture was stirred for 10 min and partitioned, which was followed bywashing with saturated brine and concentration under reduced pressure.Purification by silica gel column gave1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole (1.1 g, yield 100%).

¹H-NMR (CDCl₃, δ, 300 MHz) 1.57-1.66(2H,m), 1.86-1.97(2H,m)2.58(2H,t,J=7.5 Hz), 3.79(3H,s), 4.37(2H,t,J=7.1 Hz), 6.78-6.83(2H,m),7.01-7.06(2H,m), 7.48(1H,d,J=0.8 Hz), 7.67(1H,d,J=0.8 Hz).

EXAMPLE 21

Production of 1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole

1-(4-Aminobutyl)-4-methoxybenzene hydrochloride (1.0 g, 4.64 mmol) wasdissolved in water. Toluene (10 ml) and 2N-sodium hydroxide (10 ml) wereadded and the mixture was partitioned. The organic layer was washed with20% brine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was dissolved in methanol (8 ml) and asuspension of 2,2-dichloroacetaldehyde tosylhydrazone (2.61 g, 9.28mmol) in methanol (12 ml) was added dropwise at 15-20° C. The mixturewas stirred at room temperature for 2 hours and concentrated underreduced pressure. To the residue was added toluene (50 ml) and 2N-sodiumhydroxide (50 ml) was added with stirring. The mixture was partitioned10 min later and quantitatively measured by HPLC. As a result,1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole (417 mg) was foundto be present. yield (quantitatively measured) 39%.

EXAMPLE 22

Production of 1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole

1-(4-Aminobutyl)-4-methoxybenzene hydrochloride (1.0 g, 4.64 mmol) wasdissolved in water. Toluene (10 ml) and 2N-sodium hydroxide (10 ml) wereadded and the mixture was partitioned. The organic layer was washed with20% brine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was dissolved in methanol (8 ml), and asuspension of 2,2-dichloroacetaldehyde tosylhydrazone (2.61 g, 9.28mmol) in methanol (12 ml) was added dropwise at 15-20° C. After stirringat room temperature for 2 hours, the mixture was concentrated underreduced pressure. To the residue was added toluene (50 ml), and 25%aqueous ammonia (50 ml) was added while stirring the mixture. Themixture was partitioned 10 min later and quantitatively measured byHPLC. As a result, 1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole(829 mg) was found to be present. yield (quantitatively measured) 77%.

EXAMPLE 23

1-[4-(4-Methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole methanesulfonate

1-(4-Aminobutyl)-4-methoxybenzene hydrochloride (2.0 g, 9.27 mmol) wasdissolved in water (10 ml). Toluene (20 ml) and 2N-sodium hydroxide (10ml) were added and the mixture was partitioned. The organic layer waswashed with 20% brine (10 ml) twice, dried over anhydrous sodium sulfateand concentrated under reduced pressure. To the residue was addedmethanol (5 ml) and the mixture was concentrated under reduced pressure.The residue was dissolved in methanol (10 ml). This methanol solutionwas added dropwise to a suspension of 2,2-dichloroacetaldehydetosylhydrazone (5213 mg, 18.54 mmol) in methanol (30 ml) at 20-25° C.The mixture was stirred at room temperature for 1 hour 20 min. To themixture of toluene (20 ml) and saturated aqueous sodium hydrogencarbonate (60 ml) was added this reaction mixture, and the mixture wasstirred at room temperature for 50 min. The organic solvent wasevaporated under reduced pressure and the residue was extracted withtoluene (40 ml). 4N-Sodium hydroxide (30 ml) was added, and the mixturewas heated to 50-60° C. and partitioned. Water (30 ml) was added, andthe mixture was heated to 50-60° C. and partitioned. Water (30 ml) wasadded, and the mixture was heated to 50-60° C. and partitioned. Theorganic layer was washed with a mixture of 20% citric acid (15 ml) andsaturated brine (15 ml). After washing with saturated aqueous sodiumhydrogen carbonate (30 ml), it was washed with water (30 ml) andconcentrated under reduced pressure. The residue was dissolved in ethylacetate (10 ml) and methanesulfonic acid (0.49 ml, 7.55 mmol) was addedunder ice-cooling. Ethyl acetate (2 ml) was added and the mixture wasstirred under ice-cooling for 50 min. The precipitated crystals werecollected by filtration, washed with ice-cooled ethyl acetate (8 ml) anddried under reduced pressure to give1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole methanesulfonate(2.19 g, yield 72%).

¹H-NMR (DMSO-d₆, δ, 300 MHz) 1.40-1.51(2H,m), 1.74-1.84(2H,m)2.39(3H,s), 2.51(2H,t,J=7.7 Hz), 3.69(3H,s), 4.38(2H,t,J=7.0 Hz),6.79-6.84(2H,m), 7.04-7.09(2H,m), 7.71(1H,d,J=0.7 Hz), 8.11(1H,d,J=0.7Hz).

EXAMPLE 24

1-[4-(4-Methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole hydrochloride

1-(4-Aminobutyl)-4-methoxybenzene hydrochloride (2.0 g, 9.27 mmol) wasdissolved in water (10 ml). Toluene (20 ml) and 2N-sodium hydroxide (10ml) were added and the mixture was partitioned. The mixture was washed20% brine (10 ml) twice, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. Methanol (5 ml) was added and themixture was concentrated under reduced pressure. The residue wasdissolved in methanol (10 ml). This methanol solution was added dropwiseto a slurry of 2,2-dichloroacetaldehyde tosylhydrazone (5213 mg, 18.54mmol) in methanol (30 ml) at 20-25° C. and the mixture was stirred atroom temperature for 3 hours. The reaction mixture was poured into amixture of toluene (19 ml) and saturated aqueous sodium hydrogencarbonate (57 ml) and the mixture was stirred at room temperature for 50min. The organic solvent was evaporated by concentration under reducedpressure and the residue was extracted with toluene (40 ml). 4N-Sodiumhydroxide (30 ml) was added, and the mixture was heated to 50-60° C. andpartitioned. Water (30 ml) was added, and the mixture was heated to50-60° C. and partitioned. Water (30 ml) was added, and the mixture washeated to 50-60° C. and partitioned. The organic layer was washed with20% citric acid (15 ml), and then 3 times with water (20 ml), withsaturated aqueous sodium hydrogen carbonate (30 ml) and with water (30ml), and concentrated under reduced pressure. The residue was dissolvedin ethanol (10 ml) and concentrated hydrochloric acid (2.5 ml) wasadded. The mixture was concentrated under reduced pressure and2-propanol was added, and the mixture was concentrated under reducedpressure. Ethyl acetate was added, and the mixture was concentratedunder reduced pressure. Ethyl acetate (10 ml) was added and triturated.The mixture was stirred at room temperature for 40 min. The precipitatedcrystals were collected by filtration and dried under reduced pressureto give 1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazolehydrochloride (1.61 g, yield 68%).

¹H-NMR (DMSO-d₆, δ, 300 MHz) 1.39-1.50(2H,m), 1.73-1.83(2H,m),2.49(2H,t,J=7.6 Hz), 3.68(3H,s), 4.37(2H,t,J=7.0 Hz), 6.77-6.83(2H,m),7.02-7.07(2H,m), 7.73(1H,d,J=0.7 Hz), 8.13(1H,d,J=0.7 Hz).

Reference Example 13

Production of 4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol

1-[4-(4-Methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole methanesulfonate(4.0 g, 12.22 mmol) was added to 48% hydrobromic acid (8 ml) and themixture was heated at 80-90° C. for 6 hours. The mixture was ice-cooled,and after dropwise addition of 4N-sodium hydroxide (32 ml), washed withtoluene. 6N Hydrochloric acid was added to the aqueous layer to make pH6.3. The mixture was extracted with ethyl acetate (30 ml) andtetrahydrofuran (15 ml) and washed with water. Active charcoal (200 mg)was added, and the mixture was stirred at room temperature for 10 min.The mixture was filtrated and concentrated under reduced pressure. Ethylacetate (10 ml) was added to the residue, and the mixture was refluxed.The mixture was allowed to cool and stirred for 30 min, and hexane (10ml) was added. The mixture was stirred at room temperature for 30 min.The precipitated crystals were collected by filtration and dried underreduced pressure to give ⁴-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol (2.25g, yield 85%).

1H-NMR (CDCl₃-DMSO-d₆, δ, 300 MHz) 1.48-1.59(2H,m), 1.80-1.91(2H,m),2.49(2H,t,J=7.5 Hz), 4.31(2H,t,J=7.2 Hz), 6.68-6.73(2H,m),6.87-6.91(2H,m), 7.45(1H,d,J=0.7 Hz), 7.61(1H,d,J=0.7 Hz), 8.12(1H,s).

Reference Example 14

Production of 4-(trifluoromethyl)cinnamamide

4-(Trifluoromethyl)cinnamic acid (64.85 g, 300 mmol) was added intoluene (325 ml) and dimethylformamide (2.2 ml). Thionyl chloride (26.3ml, 361 mmol) was added dropwise at room temperature, and the mixturewas heated at 45° C. for 2 hours. The obtained reaction mixture wasadded dropwise to 25% aqueous ammonia (325 ml) while keeping the mixtureat 5-20° C. The mixture was stirred at room temperature for 1 hour. Theprecipitated crystals were collected by filtration, washed with 20 waterand isopropyl ether and dried under reduced pressure to give4-(trifluoromethyl)cinnamamide (60.76 g, yield 94%).

¹H-NMR (CDCl₃-DMSO-d₆, δ, 300 MHz) 5.93(1H,s), 6.53(1H,d,J=15.8 Hz),6.75(1H,s), 7.48-7.53(5H,m).

Reference Example 15

Production of4-(chloromethyl)-2-[(E)-2-[4-(trifluoromethyl)-phenyl]ethenyl]-1,3-oxazole

4-(Trifluoromethyl)cinnamamide (1 g, 4.65 mmol) and 1,3-dichloroacetone(1.1 g, 8.66 mmol) were added to toluene (5 ml) and the mixture wasrefluxed under heating for 8 hours. Ethyl acetate (20 ml) was added, andthe mixture was washed with water (20 ml) twice and concentrated underreduced pressure. To the residue was added methanol (4 ml) and themixture was stirred at room temperature. The crystals were filtrated anddried under reduced pressure to give4-(chloromethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole(733 mg, yield 55%).

¹H-NMR (CDCl₃, δ, 300 MHz) 4.56(2H,s), 7.01(1H,d,J=16.4 Hz),7.54-7.68(6H,m).

Reference Example 16

Production of1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole

4-[4-(1H-1,2,3-Triazol-1-yl)butyl]phenol (400 mg, 1.84 mmol) and4-(chloromethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole(529 mg, 1.84 mmol) were dissolved in dimethylformamide (3 ml),potassium carbonate (279 mg, 2.02 mmol) was added and the mixture wasstirred at 65-75° C. for 4 hours.4-[4-(1H-1,2,3-Triazol-1-yl)butyl]phenol (40 mg, 0.184 mmol) was addedand the mixture was stirred at 65-75° C. for 3 more hours. After coolingto room temperature, water (5 ml) and methanol (3 ml) were added in thisorder, and the mixture was stirred at room temperature for 40 min. Theprecipitated crystals were collected by filtration, washed with waterand dried under reduced pressure to give1-[4-[4-[[2-[(E)-2-[-4-(trifiuoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole(799 mg, yield 93%).

¹H-NMR (CDCl₃, δ, 300 MHz) 1.57-1.68(2H,m), 1.88-1.99(2H,m),2.60(2H,t,J=7.5 Hz), 4.39(2H,t,J=7.1 Hz), 5.01(2H,s), 6.89-7.08(5H,m),7.49-7.70(8H,m).

Reference Example 17

(E)-3-(4-(Trifluoromethyl)phenyl)-2-propenamide

(E)-3-(4-(Trifluoromethyl)phenyl)-2-propenoic acid (2400 g, 11.1 mol)and DMF (N,N-dimethylformamide)(82 ml) were added to toluene (12 L).SOCl₂ (52.6 mL, 721 mmol) was added dropwise at room temperature and themixture was stirred at 45-50° C. for 1 hour. The toluene solution cooledto room temperature was added dropwise to 25% aqueous ammonia (12L) at5-25° C. The mixture was stirred at 45-55° C. for 1 hour. After allowingto cool to room temperature and stirring, the mixture was stirred at thesame temperature for 1 hour. The precipitated crystals were collected byfiltration, washed with water (12 L) and dried under reduced pressure togive (E)-3-(4-(trifluoromethyl)phenyl)-2-propenamide (2293 g, 10.7 mol,yield 96%).

¹H-NMR (DMSO-d₆, δ, 300 MHz) 6.72(1H,d,J=16.1 Hz), 7.20(1H,s),7.46(1H,d,J=15.9 Hz), 7.62(1H,s), 7.67-7.83(4H,m).

EXAMPLE 25

4-(Acetoxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]-ethenyl]-1,3-oxazole

(E)-3-(4-(Trifluoromethyl)phenyl)-2-propenamide (10.0 g,46.5 mmol) and1,3-dichloroacetone (11.0 g, 86.6 mmol) were added to toluene (50 ml),and the mixture was subjected to refluxing azeotropic dehydration usinga Dean-Stark tube for 8.5 hours. The reaction mixture was concentratedunder reduced pressure. To the residue were added dimethyl sulfoxide (50ml) and sodium acetate trihydrate (15.8 g, 116.1 mmol). The mixture wasstirred at 70-75° C. for 4 hours. Methanol (50 ml) was added. Afterallowing-to cool to room temperature and stirring; the mixture wasstirred under ice-cooling for 1 hour. The precipitated crystals werecollected by filtration, washed with cold-methanol (30 ml) and driedunder reduced pressure to give4-(acetoxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole(13.1 g, yield 65%).

¹H-NMR (CDCl₃, δ, 300 MHz) 2.11(3H,s), 5.13(2H,s), 7.00(1H,d,J=16.4 Hz),7.55(1H,d,J=16.4 Hz), 7.58-7.62(5H,m).

EXAMPLE 26

4-(Acetoxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole

(E)-3-(4-(Trifluoromethyl)phenyl)-2-propenamide (950 g, 4.42 mol) and1,3-dichloroacetone (1045 g, 8.23 mol)were added to toluene (4.75 L) andthe mixture was subjected to refluxing azeotropic dehydration using aDean-Stark tube for 8 hours. During the reaction, an azeotropic mixture(2.38 L) was removed. The reaction mixture was concentrated underreduced pressure, and dimethyl sulfoxide (4.75L) and sodium acetate (905g, 11.0 mol) were added to the residue. The mixture was stirred at70-80° C. for 3.5 hours. Methanol (4.75 L) was added. After allowing tocool to room temperature and stirring, the mixture was stirred for 1hour under ice-cooling. The precipitated crystals were collected byfiltration, washed with cold-methanol (1.9 L), and dried under reducedpressure to give4-(acetoxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole(1560 g, yield 51%).

EXAMPLE 27

1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole

4-(Acetoxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole(20.0 g, 64.3 mmol) was dissolved in dimethyl sulfoxide (200 ml), and2N-aqueous sodium hydroxide solution (35 mL 70.0 mmol) was added at 50°C. The mixture was stirred at about 40° C. for 15 min. Water (200 ml)was added at the same temperature. After allowing to cool to roomtemperature and stirring, the mixture was stirred at the sametemperature for 1 hour. The precipitated crystals were collected byfiltration, washed with water (60 ml) and dried under reduced pressureto give4-(hydroxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole(16.4 g, 61.1 mmol, yield 95%).

The obtained4-(hydroxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole(1.00 g, 3.71 mmol) and diisopropylethylamine (0.95 mL, 5.44 mmol) wereadded to THF (tetrahydrofuran) (15 ml). Methanesulfonyl chloride (0.45mL, 5.81 mmol) was added dropwise under ice-cooling. The mixture wasstirred at the same temperature for 1 hour.4-[4-(1H-1,2,3-Triazol-1-yl)butyl]phenol (900 mg, 4.14 mmol) andtetra(n-butyl)ammonium bromide (60 mg, 0.19 mmol) were added at the sametemperature. A 2N aquous sodium hydroxide solution (7.5 mL, 15.0 mmol)was added dropwise at not more than 15° C. and the mixture was stirredwith reflux for 1 hour. After allowing to cool to room temperature andstirring, the organic layer was concentrated under reduced pressure.Ethanol (20 ml) was added to the residue, and the mixture was stirredwith reflux. Water (20 ml) was added dropwise at the same temperature.After allowing to cool to room temperature and stirring, the mixture wasice-cooled. The precipitated crystals were collected by filtration,washed with water (20 ml) and dried under reduced pressure to give1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole(1.61 g, 3.44 mmol, yield 88%).

¹H-NMR (CDCl₃, δ, 300 MHz) 1.57-1.68(2H,m), 1.88-1.99(2H,m)2.60(2H,t,J=7.5 Hz), 4.39(2H,t,J=7.1 Hz), 5.01(2H,s), 6.89-7.08(5H,m),7.49-7.70(8H,m).

EXAMPLE 28

1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole

4-(Acetoxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]-ethenyl]-1,3-oxazole(1556 g, 2.23 mol), 2N-aqueous sodium hydroxide solution (2.4 L, 4.8mol) and activated carbon (47 g) were added to methanol (4.7 L), and themixture was refluxed under stirring for 1 hour. The activated carbon andthe insoluble material were removed by filtration under pressurization.The residue was washed with methanol/water (2:1) (470 ml). The washingsolution was combined with the filtrate and the mixture was refluxed.Water (3.3 L) was added at the same temperature. After allowing to coolto room temperature and stirring, the mixture was stirred at the sametemperature for 1 hour. The precipitated crystals were collected byfiltration, washed with water (4.7 L) and dried under reduced pressureto give4-(hydroxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole(568.5 g, 2.11 mol, yield 95%).

The obtained4-(hydroxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole(567 g, 2.11 mol) and diisopropylethylamine (340 g, 2.63 mol) were addedto THF (3.4 L). A solution of methanesulfonyl chloride (302 g, 2.63 mol)in THF (567 ml) was added dropwise under ice-cooling. The mixture wasstirred at the same temperature for 1 hour and diisopropylethylamine(27.3 g, 0.21 mol), methanesulfonyl chloride (24.2 g, 0.21 mol) and THF(57 ml) solution were added. The mixture was stirred under reflux for1.5 hours. After allowing to cool to room temperature, 15% aqueoussodium hydroxide (1.96 kg, 7.35 mol) was added dropwise.4-[4-(1H-1,2,3-Triazol-1-yl)butyl]phenol (503 g, 2.32 mol) andtetra(n-butyl) ammonium bromide (68.0 g, 0.21 mol) were added at thesame temperature, and the mixture was refluxed for 4 hours understirring. Water (3.1 L) and methanol (7.4 L) were added dropwise at thesame temperature. After allowing to cool to room temperature, themixture was stirred at the same temperature for 1 hour. The precipitatedcrystals were collected by filtration, washed with THF/methanol/water(1:1:2) (2.8 L), water (2.8 L) and cold-methanol (2.8 L) and dried underreduced pressure to give1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole(883 g, 1.88 mol, yield 85%).

Reference Example 18

4-(Hydroxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole

(E)-3-(4-(Trifluoromethyl)phenyl)-2-propenamide (20.0 g, 92.9 mmol) wasadded to toluene (75 ml), and 1,3-dichloroacetone (22.0 g, 173.3 mmol)and toluene (25 ml) were added. The mixture was subjected to refluxingazeotropic dehydration for 9 hours. The reaction mixture was dividedinto two equal portions and one of them was concentrated under reducedpressure. To the residue were added dimethyl sulfoxide (100 ml), sodiumacetate trihydrate (15.9 g, 116.8 mmol) and water (20 ml). The mixturewas stirred at 70-75° C. for 4.5 hours. 2N-Aqueous sodium hydroxidesolution (60 ml) was added at the same temperature and the mixture wasstirred for 1 hour. After allowing to cool to room temperature, toluene(400 ml) and water (400 ml) were added and the mixture was partitioned.After washing with 5% brine (200 ml), the organic layer was concentratedunder reduced pressure. To the residue was added methanol (10 ml) andthe mixture was heated to 60° C. to allow dissolution. After allowing tocool to room temperature and stirring, the mixture was stirred for 1hour under ice-cooling. The precipitated crystals were collected byfiltration, washed with cold-methanol (5 ml) and dried under reducedpressure to give4-(hydroxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]-ethenyl]-1,3-oxazole(5.96 g, 22.1 mmol, yield 48%).

¹H-NMR (CDCl₃, δ, 300 MHz) 2.83(1H,s), 4.69(2H,d,J=5.2 Hz),6.96(1H,d,J=13.1 Hz), 7.51(1H,d,J=12.7 Hz), 7.55-7.66(5H,m).

Reference Example 19

4-(Hydroxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]-ethenyl]-1,3-oxazole

(E)-3-(4-(Trifluoromethyl)phenyl)-2-propenamide (4.30 g, 20.0 mmol) and1,3-dichloroacetone (4.75 g, 37.4 mmol) were added to toluene (20 ml)and the mixture was subjected to refluxing azeotropic dehydration usinga Dean-Stark tube for 6 hours. The reaction mixture was allowed to coolto room temperature, and DMF (50 ml), water (30 ml) and potassiumcarbonate (13.7 g, 99.1 mmol) were added. The mixture was stirred at100° C. for 1.5 hours. After allowing to cool to room temperature, ethylacetate (200 ml) and water (150 ml) were added and the mixture waspartitioned. The organic layer was washed with water/saturated brine(1:1, 100 ml). To the organic layer was added ethyl acetate (400 ml),and the mixture was washed with water (200 ml) twice and concentratedunder reduced pressure. Ethanol (30 ml) was added to the residue. Water(38 ml) was added and the precipitated crystals were collected byfiltration, washed with water (40 ml) and dried under reduced pressureto give4-(hydroxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole(3.3 g, 3.71 mmol, yield 62%).

Reference Example 20

[2-[(E)-2-[4-(Trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methylmethanesulfonate

4-(Hydroxymethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]-ethenyl]-1,3-oxazole(5.0 g, 18.6 mmol) and triethylamine (3.1 mL, 22.4 mmol) were added toTHF solution (25 ml), and methanesulfonyl chloride (1.8 mL, 23.3 mmol)was added dropwise under ice-cooling. THF (25 ml) was added at the sametemperature and the mixture was stirred for 40 min. The mixture wasstirred at room temperature for 1 more hour. To the mixture was addedwater (25 ml) and the mixture was extracted with ethyl acetate (25 ml).The organic layer was washed with water (25 ml). The aqueous layers werecombined and extracted with ethyl acetate (25 ml). The organic layerswere combined and concentrated. Ethyl acetate (40 ml) and isopropylether (10 ml) were added to the→residue. The mixture was heated to 60°C. for dissolution. After allowing to cool to room temperature withstirring, isopropyl ether (10 ml) was added under ice-cooling and theprecipitated crystals were collected by filtration. The crystals werewashed with isopropyl ether (10 ml) and dried under reduced pressure togive[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methylmethanesulfonate(5.1 g, 14.5 mmol, yield 78%).

¹H-NMR (CDCl₃, δ, 300 MHz) 3.09(3H,s), 5.22(1H,s), 7.00(1H,d,J=16.4 Hz),7.57(1H,d,J=16.4 Hz), 7.60-7.69(4H,m), 7.78(1H,s).

Reference Example 21

1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole

[2-[(E)-2-[4-(Trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methylmethanesulfonate(500 mg, 1.44 mmol), 4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol (344 mg,1.58 mmol) and tetra(n-butyl) ammonium bromide (45 mg, 0.14 mmol) wereadded to THF (5 ml), and 1N-aqueous sodium hydroxide solution (3.0 mL,3.00 mmol) was added. The mixture was stirred at room temperature for 5hours. 10% Brine (10 ml) was added and the mixture was extracted withethyl acetate (10 ml). The organic layer was washed with 10% brine (10ml). The aqueous layers were combined and extracted with ethyl acetate(10 ml). The organic layers were combined and concentrated. Ethanol (15ml) was added to the residue and the mixture was refluxed under heatingfor dissolution. After allowing to cool to room temperature andstirring, the mixture was stirred for 1 hour under ice-cooling. Theprecipitated crystals were collected by filtration, washed withcold-ethanol (2 ml) and dried under reduced pressure to give1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole(556 mg, 1.19 mmol, yield 81%).

EXAMPLE 29

1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole

(E)-3-(4-(Trifluoromethyl)phenyl)-2-propenamide (4.00 g, 18.59 mmol) and1,3-dichloroacetone (3.54 g, 27.89 mmol) were added to toluene (14 ml)and the mixture was subjected to refluxing azeotropic dehydration usinga Dean-Stark tube for 3 hours. A solution of sulfuric acid (91 mg) intoluene (1 ml) was added at the same temperature and the mixture wasfurther subjected to refluxing azeotropic dehydration for 3.5 hours. Thereaction mixture was concentrated under reduced pressure, and THF (20ml) and tetra(n-butyl) ammonium bromide (428 mg, 1.328 mmol) were addedto the residue. 30% Aqueous potassium hydroxide solution (12.42 g, 66.4mmol) was added dropwise at 20-30° C. and the mixture was stirred at thesame temperature for 15 min. 4-[4-(1H-1,2,3-Triazol-1-yl)butyl]phenol(2.89 g, 13.28 mmol) was added and the mixture was refluxed understirring for 2 hours. Water (13.4 ml) and methanol (20 ml) were addeddropwise at the same temperature. After allowing to cool to roomtemperature and stirring, the mixture was stirred at the sametemperature for 1 hour. The precipitated crystals were collected byfiltration, washed with cold-methanol (40 ml) and dried under reducedpressure to give1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole(5.35 g, 11.42 mmol, yield 86%).

Reference Example 22

Production of1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)-phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole

1-[4-[4-[[2-[(E)-2-[4-(Trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole(5.0 g) was added to water/1-propanol=1/9 (65 ml), and active charcoal(100 mg) was added. After refluxing under heating, an insoluble materialwas filtered off while hot, and the residue was washed withwater/1-propanol=1/9 (5 ml). The filtrate was refluxed again and wasallowed to cool and stirred at 50° C. to 55° C. for 30 min. Water (56ml) was added dropwise at the same temperature and the mixture wasstirred at from 50° C. to 60° C. for 20 hours. The crystals werefiltrated, washed with water (50° C.) and dried under reduced pressureat 40° C. to give1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]-phenyl]butyl]-1H-1,2,3-triazole(4.29 g, yield 92%) as crystals (the same crystals as those obtained inExample 4 of Japanese Patent Application No. 2000-108204).

The crystals were analyzed by powder X ray diffraction, the results ofwhich are shown in the following.

The crystals showed a powder X ray diffraction pattern showingcharacteristic peaks at diffraction angles (2θ) of powder X raydiffraction of 15.88, 21.22 and 21.82 degrees. The powder X raydiffraction chart is shown in FIG. 1.

EXAMPLE 30

Production of1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)-phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole

1-[4-[4-[[2-[(E)-2-[4-(Trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole(150.0 g) was added to acetone (1.5 L). The mixture was refluxed underheating and the insoluble material was filtered off. The residue waswashed with acetone (60 ml) and the filtrate and the washing solutionwere refluxed. Water (150 ml) was added dropwise under reflux. Themixture was allowed to cool and stirred at 30° C. Water (390 ml) wasadded dropwise and the mixture was stirred at room temperature for 2hours and under ice-cooling for 5.5 hours. The reaction mixture wasfiltrated, washed with ice-cooled acetone/water=1/1 (300 ml×2) and driedunder reduced pressure at 40° C. to give1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]-phenyl]butyl]-1H-1,2,3-triazole as crystals(141.4 g, yield 94%).

The crystals were analyzed by powder X ray diffraction, the results ofwhich are shown in the following.

The crystals showed a powder X ray diffraction pattern showingcharacteristic peaks at diffraction angles (20) of powder X raydiffraction of 6.98, 14.02, 17.56, 21.10 and 24.70 degrees. The powder Xray diffraction chart is shown in FIG. 2.

Reference Example 23

Production of1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]-ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazolemethanesulfonate

1-[4-[4-[[2-[(E)-2-[4-(Trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole(1.0 g) was dissolved in ethyl acetate (50 ml) and tetrahydrofuran (5ml). A solution of methanesulfonic acid (205 mg) in tetrahydrofuran (5ml) was added dropwise. The crystals were precipitated. The mixture wasstirred at room temperature for 20 min and under ice-cooling for 50 min.The reaction mixture was concentrated under reduced pressure until theliquid amount became about half. After stirring the mixture underice-cooling for 30 min, the mixture was filtrated, washed with ethylacetate/isopropyl ether=1/1 (3 ml) and dried under reduced pressure (40°C.) to give 1-[4-[4-[ [2-[(E)-2-[4-(trifluoromethyl)-phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazolemethanesulfonate (1.18 g, yield 98%).

1H-NMR (300 MHz, CDCl₃, δ) 1.61-1.69(2H,m), 1.94-2.05(2H,m),2.62(2H,t,J=7.35 Hz),2.90(3H,s),4.51(2H,t,J=7.14 Hz)5.05(2H,s),6.91-7.13(5H,m),7.60-7.74(6H,m),7.97(1H,s),8.16(1H,s).

Reference Example 24

Production of1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]-ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazolep-toluenesulfonate

1-[4-[4-[[2-[(E)-2-[4-(Trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole(1.0 g) was dissolved in ethyl acetate (50 ml) and tetrahydrofuran (5ml). A solution of p-toluenesulfonic acid monohydrate (406 mg) intetrahydrofuran (5 ml) was added dropwise. The crystals wereprecipitated. The mixture was stirred at room temperature for 2 hours 20min and filtrated. The mixture was washed with ethyl acetate/isopropylether=1/1 (3 ml) and dried under reduced pressure (40° C.) to give1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazolep-toluenesulfonate (1.1 g, yield 80%).

¹H-NMR (300 MHz, CDCl₃, δ) 1.58-1.66(2H,m), 1.90-2.01(2H,m),2.31(3H,s),2.59(2H,t,J=7.28 Hz), 4.49(2H,t,J=7.06 Hz), 5.05(2H, s),6.88-7.19(7H,m),7.61-7.81(8H,m), 8.02(1H,s), 8.16(1H,s).

Reference Example 25

Production of1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]-ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazolebenzenesulfonate

1-[4-[4-[[2-[(E)-2-[4-(Trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole(1.0 g) was dissolved in ethyl acetate (50 ml) and tetrahydrofuran (5ml). A solution of benzenesulfonic acid monohydrate (376 mg) intetrahydrofuran (5 ml) was added dropwise. The crystals wereprecipitated. The mixture was stirred room temperature for 2 hours andfiltrated. The mixture was washed with ethyl acetate/isopropyl ether=1/1(3 ml) and dried under reduced pressure (40° C.) to give1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)-phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazolebenzenesulfonate (1.05 g, yield 78%).

¹H-HNR (300 MHz, CDCl₃+DMSO-d₆, δ) 1.54-1.66(2H,m), 1.88-1.99(2H,m),2.58(2H,t,J=7.47 Hz), 4.44(2H,t,J=7.17 Hz), 5.00(2H,s),6.87-7.06(5H,m),7.39-7.44(3H,m),7.53-7.70(6H,m), 7.80(1H,s), 7.87-7.91(2H,m),7.99(1H,s).

Reference Example 26

Production of1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]-ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazolesulfate

1-[4-[4-[[2-[(E)-2-[4-(Trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole(1.0 g) was dissolved in ethyl acetate (50 ml) and tetrahydrofuran (5ml). A solution of sulfuric acid (209 mg) in tetrahydrofuran (5 ml) wasadded dropwise. The crystals were precipitated. The mixture was stirredat room temperature for 40 min and filtrated. The mixture was washedwith ethyl acetate (3 ml) and dried under reduced pressure (40° C.) togive1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]-phenyl]butyl]-1H-1,2,3-triazolesulfate (1.13 g, yield 93%).

¹H-HNR (300 MHz, CDCl₃+DMSO-d₆, δ) 1.56-1.66(2H,m), 1.89-2.00(2H,m),2.60(2H,t,J=7.50 Hz), 4.45(2H,t,J=7.11 Hz),5.00(2H,s), 6.88-7.10(5H,m),7.53-7.70(5H,m), 7.93(1H,s), 7.82(1H,s), 7.85(1H,s).

Reference Example 27

Production of1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]-ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazolehydrochloride

1-[4-[4-[[2-[(E)-²-[4-(Trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole(1.5g) was dissolved in tetrahydrofuran (75 ml). Concentrated hydrochloricacid (0.3 ml) was added dropwise. The crystals were precipitated. Themixture was stirred at room temperature for 40 min and filtrated. Themixture was washed with ethyl acetate (3 ml) and dried under reducedpressure (40° C.) to give1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazolehydrochloride(1.09 g, yield 67%).

¹H-HNR (300 MHz, CDCl₃+DMSO-d₆, δ) 1.60-1.66(2H,m), 1.93-1.98(2H,m),2.61(2H,t,J=7.53 Hz), 4.43(2H,t,J=7.08 Hz), 5.03(2H,s), 6.90-7.09(5H,m),7.55-7.81(8H,m).

Industrial Applicability

According to the production methods of the present invention,1-substituted-1,2,3-triazole compounds having a tyrosine kinase(especially HER2) inhibitory action can be produced efficiently in ahigh yield at an industrial large scale by a convenient method.

What is claimed is:
 1. A method for producing a compound of the formula:

wherein R^(a1) and R^(a2) are each a hydrogen atom, a substitutedhydroxy, a substituted thiol, a substituted amino, an optionallysubstituted hydrocarbon group, or an acyl; R^(a3) is a group of theformula:

wherein R^(a4) and R^(a5) are each a hydrogen atom, an optionallysubstituted hydroxy, an optionally substituted thiol, an optionallysubstituted amino, an optionally substituted hydrocarbon group, or anacyl, or R^(a4) and R^(a5) in combination form oxo, R^(a6) an optionallysubstituted aromatic group, and m^(a) is an integer of 0 to 10; or twoor three from R^(a1), R^(a2) and R^(a3) form an optionally substitutedring, together with the adjacent carbon atom; and R^(a7) and R^(a8) areeach a hydrogen atom, a halogen, an optionally substituted hydroxy, anoptionally substituted thiol, an optionally substituted amino, anoptionally substituted hydrocarbon, or an acyl, which method comprisesreacting a compound of the formula:

wherein X^(a) is a leaving group and other symbols are as defined above,or a salt thereof, and compound of the formula:

wherein each symbol is as defined above, or a salt thereof, (1) in asecondary or tertiary alcohol in the presence of a base, or (2) in theabsence of a base.
 2. The production method of claim 1, which comprisesreaction in a secondary or tertiary alcohol in the presence of a base.3. The production method of claim 1, which comprises reaction in atertiary alcohol in the presence of a base.
 4. The production method ofclaim 1, wherein R^(a1) is a hydrogen atom.
 5. The production method ofclaim 1, wherein R^(a1) and R^(a2) are each a hydrogen atom.
 6. Theproduction method of claim 1, wherein R^(a3) is a group of the formula:

wherein each symbol is as defined in claim
 1. 7. The production methodof claim 6, wherein R^(a4) and R^(a5) are each a hydrogen atom.
 8. Theproduction method of claim 6, wherein R^(a6) is an optionallysubstituted phenyl.
 9. The production method of claim 6, wherein m^(a)is
 3. 10. The production method of claim 1, wherein R^(a7) and R^(a8)are each a hydrogen atom.
 11. The production method of claim 1, whereinR^(a1), R^(a2), R^(a7) and R^(a8) are each a hydrogen atom and R^(a3) is3-[4-(t-butoxyphenyl)]propyl.